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94 2d slsSm* } HOUSE COMMITTEE PRINT NO. 119 



MEDICAL RESEARCH IN THE 
VETERANS' ADMINISTRATION 



FOR THE YEAR BEGINNING JULY 1, 1974, 

AND ENDING JUNE 30, 1975 

(FISCAL YEAR 1975) 




APRIL 15, 197^<§?/ 



|S JAN 



1978 



^ms$/ 



Printed for the use of the Committee on Veterans' Affairs 



70-799 



U.S. GOVERNMENT PRINTING OFFICE 
WASHINGTON : 1976 



£< 



V 



COMMITTEE OX VETERANS' AFFAIRS 
RAY ROBERTS, Texas, Chairman 

OLIN E. TEAGUE, Texas EDWARD P. BEARD. Rhode Island 

DAVID E. SATTERFIELD III, Virginia ROBERT W. EDGAR, Pennsylvania 

DON EDWARDS. California KENNETH L. HOLLAND, South Carolina 
G. V. (SONNY) MONTGOMERY, Mississippi MATTHEW F. McHUGH. New York 

CHARLES J. CARNEY, Ohio JOHN PAUL HAMMERSCHMIDT, Arkansas 

GEORGE DANIELSON, California MARGARET M. HECKLER, Massachusetts 

LESTER L. WOLFF, New York CHALMERS P. WYLIE, Ohio 

JACK BRINKLEY, Georgia ELWOOD HILLIS, Indiana 

RONALD M. MOTTL, Ohio JAMES ABDNOR, South Dakota 

ROBERT J. CORNELL, Wisconsin WILLIAM F. WALSH, New York 

W. G. (BILL) HEFNER, North Carolina TENNYSON GUYER, Ohio 

MARK W. HANNAFORD, California GEORGE HANSEN. Idaho 

CLIFFORD ALLEN, Tennessee GEORGE M. O'BRIEN, Illinois 

Oliver E. Meadows, Staff Director 

Subcommittee 

Compensation, Pension and Insurance 

G. V. (SONNY) MONTGOMERY, Mississippi, Chairman 

OLIN E. TEAGUE, Texas RONALD M. MOTTL, Ohio 

RAY ROBERTS, Texas CHALMERS P. WYLIE, Ohio 

JACK BRINKLEY, Georgia JOHN PAUL HAMMERSCHMIDT, Arkansas 

W. G. (BILL) HEFNER, North Carolina TENNYSON GUYER, Ohio 

Education and Training 
OLIN E. TEAGUE, Texas, Chairman 

LESTER L. WOLFF, New York KENNETH L. HOLLAND, South Carolina 

RONALD M. MOTTL, Ohio CLIFFOD ALLEN, Tennessee 

ROBERT J. CORNELL, Wisconsin MARGARET M. HECKLER, Massachusetts 

MARK W. HANNAFORD, California CHALMERS P. WYLIE, Ohio 

ROBERT W. EDGAR, Pennsylvania WILLIAM F. WALSH, New York 

(II) 



Ill 



Hospitals 

DAVID E. SATTERFIELD III, Virginia, Chairman 



DON EDWARDS. California 

G. V. (SONNY) MONTGOMERY. Mississippi 

CHARLES J. CARNEY, Ohio 

GEORGE DANIELSON. California 

LESTER L. WOLFF, New York 

CLIFFORD ALLEN. Tennessee 

EDWARD P. BEARD, Rhode Island 

W. G. (BILL) HEFNER, North Carolina 

MARK W. HANNAFORD, California 

KENNETH L. HOLLAND. South Carolina 



MATTHEW F. McHUGH, New York 

RONALD M. MOTTL, Ohio 

JOHN PAUL HAMMER SCHMIDT, Arkansas 

MARGARBT M. HECKLER, Massachusetts, 

ELWOOD HILLIS, Indiana 

JAMES AJ3DNOR, South Dakota 

TENNYSON GUYER, Ohio 

GEORGE HANSEN, Idaho 

GEORGE M. O'BRIEN, Illinois 



Housing 

JACK BRINKLEY, Georgia, Chairman 



CHARLES J. CARNEY. Ohio 
DAVID E. SATTERFIELD III, Virginia 
DON EDWARDS, California 
ROBERT J. CORNELL, Wisconsin 



EDWARD P. BEARD, Rhode Island 
JAMES ABDNOR. South Dakota 
WILLIAM F. WALSH, New York 



Cemeteries and Burial Benefits 
GEORGE DANIELSON, California, Chairman 



RAY ROBERTS, Texas 

ROBERT W. Edgar, Pennsylvania 

MATTHEW F. McHUGH, New York 

ROBERT J. CORNELL, Wisconsin 

W. G. (BILL) HEFNER, North Carolina 

MARK W. HANNAFORD, California 



CLIFFORD ALLEN, Tennessee 

EDWARD P. BEARD, Rhode Island 

ELWOOD HILLIS, Indiana 

JOHN PAULHAMMERSCHMIDT, Arkansas 

GEORGE HANSEN, Idaho 

GEORGE O'BRIEN, Illinois 



Digitized by the Internet Archive 
in 2013 



http://archive.org/details/meresearchi42unit 



CONTENTS 



Pa pre 

Letter of transmittal ix 

Foreword xi 

VA central office research staff xiir 

Highlights of VA research accomplishments 1 

VA participation in conferences 6 

National and international awards 8 

William S. Middleton Award 8 

Abbreviated history 10 

Medical research advisory committees 11 

Administrative data 12 

Medical research career development program 12 

Senior medical investigator program 12 

Medical investigator program 14 

Clinical investigator program 14 

Research associate program 14 

Psychology research associate program 14 

Advanced specialty training program 15 

Research program 15 

Health services research and development 15 

Prosthetics research program 17 

Clinical research 18 

Aging 18 

Alcohol and drug dependence 20 

Audiology and speech pathology 22 

Cardiovascular disorders 22 

Atherosclerotic heart disease 23 

Basic science research 24 

Cardiovascular surgery 25 

Complications .> 26 

Graphic techniques 27 

Endocrinology and metabolism 28 

Diabetes mellitus 28 

Calcium and bone disease 29 

Atherosclerosis and lipid disorders 29 

Alcoholism 30 

Arthritis 30 

Gastroenterology 30 

Esophagus and stomach 31 

Pancreas and the biliary tract 32 

Liver 33 

Small intestine and large colon 34 

Hematology and sickle cell disease 34 

Anemias, hemoglobin and sickle cell anemia 34 

Vitamin B i2 and pernicious anemia 36 

Bleeding disorders, platelets and blood coagulation 37 

Immunology 38 

Connective tissue diseases 38 

Pulmonary disease 38 

Malignancy 39 

Basic investigations 39 

(V) 



VI 

Research program — Continued 

Clinical research — Continued Pa s e 

Infectious diseases 40 

Bacterial infections 40 

Infections with organisms other than bacteria 42 

Host defense mechanisms against infection 4M 

Therapy and prophylaxis 4M 

Allergy 43 

Mental health and behavioral sciences 44 

Nephrology 40 

Prevention of kidney disease 46 

Treatment of kidney disease — 47 

Dialysis, transplantation, and treatment of uremia 48 

Kidney function in health and disease 50 

Neurology and neurobiology T»2 

Multiple sclerosis 52 

Virus infections 53 

Recovery from stroke 53 

Sensory and perceptual disorders 54 

Nuclear medicine and radiation 54 

Instrumentation 54 

Radiopharmacy 54 

Tumor diagnosis and treatment •">" 

Central nervous system 58 

Cardiovascular studies 58 

Miscellaneous 59 

Nursing research 59 

Oncology 00 

The VA-NCI medical oncology branch 63 

Oral biology 68 

Pathology 6.~ 

Rehabilitation medicine 66 

Respiration and pulmonary diseases ON 

Social sciences 72 

Spinal cord disorders 74 

Surgery 70 

Vision 81 

Multihospital research 82 

Cooperative studies 82 

Cancer 82 

Lung cancer therapy 82 

Surgical adjuvant cancer therapy 83 

Urological research group 84 

Brain tumor cooperative group 84 

Radiotherapy versus surgery or delayed hormonal therapy in 

treatment of prostatic carcinoma 85 

Internal medicine 85 

Antihypertensive agents 85 

Hepatitis 86 

Crohn's disease 87 

Mental health and behavioral sciences | 87 

Social sciences 87 

Drug-abuse prevention 87 

Characteristics of effective psychiatric programs 88 

Pulmonary diseases 88 

Chemoprophylaxis of tuberculosis 88 

Speech pathology , 88 

Treatment of aphasia 88 

Surgery . 89 

Analgesics 89 

Coronary arterial disease 89 

Ksophageal and gastric varices <M> 

Bowel preparation for colon operations 90 

Pathogenic significance of sickle-cell trait 90 

Aspirin therapy and unstable angina 01 

Vasodilator therapy of myocardial infarction f)l 

Quality control of lab data <>1. 

Drugs and sleep , 01 



VII 

Page 

NAS-NRC followup agency 92 

Survey of mortality of former prisoners of war (VA) 92 

Surgical adjuvant cancer chemotherapy study ( VA) 93 

Thirtv-vear clinical followup of selected demyelinating diseases 

(VA) 94 

Longitudinal study of cardiovascular disease (VA) 94 

Microwave cataract screening (VA) 95 

Monitoring records resources (VA) 95 

Medical genetic studies of veteran twins (XIH) 96 

Epidemiologic study of multiple sclerosis in U.S. military veteran 

population (NIH) 97 

Epidemiologic and followup study of amyotrophic lateral sclerosis and 

other motor neuron diseases (XIH) 98 

Epidemiology of Hodgkin's disease (XIH) 98 

Causes of death following occupational exposure to microwave radia- 
tion (RADAR) (Bureau of Radiological Health) 99 

Cancer mortality among World War II X-ray technicians (Bureau of 

Radiological Health) 99 

Epidemiology of childhood cancer, with reference to prenatal X-ray 

(XIH) 99 

Followup studies of World War II veterans with certain conditions 

possibly related to cancer (XIH) 100 



LETTER OF TRANSMITTAL 



Veterans' Administration, 
Washington, D.C., April 15, 1976. 
Hon. Ray Roberts, 

Chairman, Committee on Veterans' 1 Affairs, House of Representatives, 
Washington, D.C. 
Dear Mr. Chairman : I am pleased to send you this 20th Annual 
Report of Medical Research in the Veterans' Administration for the 
fiscal year 1975. Thanks to your committee's support we may present 
it as a way station on a continuous journey of discovery through two 
decades of scientific endeavor oriented to improve the quality of health 
care delivered to our veterans in almost every medical discipline. The 
general acceptance of the improved clinical practices resulting from 
VA medical research not only pays tribute to the soundness of the 
research but, more importantly, delivers better health care to persons 
of all ages everywhere. 
Sincerely, 

Richard L. Roudebush, Administrator. 

(IX) 



FOREWORD 



During fiscal year 1975, medical research in the Veterans Adminis- 
tration continued its attack on humanity's greatest killers as well as on 
the multiplicity of injuries and illnesses that plague our veterans and 
the community at large. 

Supported by state and local heart associations, a Long Beach. Calif. 
VA cardiologist and his colleagues directed the screening of 2,524 
Long Beach citizens with no history of heart disease. They evaluated 
six major risk factors known to predispose people to coronary heart 
disease. Results were given to subjects and their physicians, with brief- 
ings of those considered to be serious risks. The study showed that the 
best approach to the epidemic of coronary heart disease is prevention ; 
first, by detecting the presence of risk factors, then beginning long- 
term treatment. 

The VA Cooperative Study Group on Antihypertensive Agents — 
largely responsible for world-wide efforts to discover and treat high 
blood pressure — found that a small number of older persons with 
initial records near the lower limit of high blood pressure, after two 
years or more of medical management which put them within the nor- 
mal range, may remain normal indefinitely, even if medication is 
stopped. 

Radioimmunoassay — a discovery of the Solomon A. Berson Re- 
search Laboratory, Bronx VA Hospital, Xew York City — made pos- 
sible the further discovery by investigators at the Berson Laboratory 
and in the Pulmonary Disease Section, VA Hospital. East Orange, 
X.J., that lung cancer tumor cells produce u Big ACTH, r and adreno- 
corticotrophic hormone of giant molecules compared to the same 
hormone produced by the pituitary gland. When the primary site of 
the tumor is unknown, the probability of the site being in the lung is 
favored if "Big ACTH" can be detected in the tissue. Now the disease 
may be found early enough for successful treatment in many cases, and 
the new discovery may also be used to evaluate the success of the treat- 
ment. Lung cancer is the most common cancer among males. 

A San Francisco VA Hospital research biologist, studying cell-walls 
of normal and cancerous human breast tissue with the scanning elec- 
tron microscope, made a breakthrough in the diagnosis of breast 
eanceri She found that certain cells lining ducts in normal breast tissue 
were covered with microvilli (tiny hair-like projections) that gave 
them a brush-like appearance when magnified up to 10,000 times. In 
cancerous tissue, however, the microvilli were enlarged and clumped 
together and exhibited other irregularities making the cancer tissue 
identifiable at a glance. 

A microbiologist at the VA Hospital. Salt Lake City. Utah demon- 
strated how macrophages — large scavenger cells of the immune sys- 

(XI) 



XII 

tern — may be activated by immunological agents, such as bacillus 
Calmette Guerin (BCG), a tuberculosis vaccine, so that a change 
occurs — perhaps in their cell-walls — and the macrophages destroy 
.cancer cells in a test tube culture. 

The Normative Aging Study at the Boston VA Outpatient Clinic 
-gives encouragement to the aging. Indications are that adaptation to 
aging, and even the aging process itself, unlike disease or injury, is to 
some degree under the control of the individual. Choices of diet, ex- 
ercise, habits of drinking and smoking, and life-style may lend an 
advantage to coping with advancing age. In optimal health care for the 
aging, the study suggests that a gerontologist should include counseling 
and education calculated to involve the individual in beneficial activity 
as well as any necessary treatment for disease or injury. 

Investigators at the Bronx VA Hospital, New York City found that 
large doses of vitamin C may destroy 50 to 95 percent of the vitamin 
B 12 contained in a meal. Vitamin B 12 is the most potent defense 
known against pernicious anemia. Concerned about pain following 
chest surgery, which prevents patients from coughing and breathing 
deeply enough to avoid pulmonary complications, surgeons at the VA 
Hospital, Albuquerque, New Mex. froze nerves between the ribs, per- 
mitting a painless convalescence with a return to normal sensation 
after about six months. 

The VA Prosthetics Center in New York City has developed a num- 
ber of myoelectrically controlled hooks, capable of unusually high 
grasping force to supplant amputated hands. The Center also has 
tested prototypes of a unique combination power-bed and wheelchair. 
These permit a helpless patient without the use of arms or legs to 
have independent mobility within a hospital or around a ranch-style 
home and patio. The Center has designed and made ambulators which 
permit a patient, who cannot stand independently, to work in the 
upright position and move voluntarily for short distances on level 
surfaces. These devices also allow activity in narrow spaces which do 
not admit a wheelchair. 

VA investigators have made progress in preventing the type of 
blood vessel disease that causes the loss of limbs. They have had in- 
creasing success, when surgery is necessary, in operating below the 
knee and often at the ankle, in contrast to the older amputations of 
the entire leg. Immediate post-surgical prosthetics management re- 
sults in quicker rehabilitation and discharge of patients, and the cost 
of an artificial foot is substantially below the cost of an artificial leg. 

VA medical research continues to be productive in providing new 
knowledge helpful to veterans and other individuals in meeting their 
health needs. It provides an irreplaceable support to the medical care 
of veterans in that it assists in the recruitment of outstanding clini- 
cians and finally, it demonstrates the merit of pursuing the answers 
to relevant questions in a setting that provides the capability for the 

rapid application of these advancements to the individual patient It 

continues to be recognized by the world scientific community as evi- 
denced in (he Honors and Awards Section of this report.. 

John D. Citase, M.D., 

Chief Medical Director. 



VETERANS' ADMINISTRATION CENTRAL OFFICE RESEARCH STAFF 
Office of the ACMD for Research and Development 

Newcomb, Thomas F., M.D., Assistant Chief Medical Director for R&D 

Hobson, Lawrence B., M.D., Ph.D., Deputy Assistant Chief Medical Director for 

R&D 
Bazel, Chester G., Administrative Officer for R&D 
Cortright, Everett S., Staff Assistant for Prosthetics Research 

Medical Research Service 

Hays, Marguerite T., M.D., Director, Medical Research Service 
Dury, Abraham, Ph.D., Deputy Director, Medical Research Service 
Tippets, Wayne C, Administrative Officer, Medical Research Service 
Bowman, Russell D., Chief, Scientific Communications Unit 
Cass, Jules S., D.V.M., Veterinary Medical Officer 
Hagans, James A., M.D., Ph.D., Chief, Cooperative Studies Unit 
Hine, Gerald J., Ph.D., Chief, Medical Instrument Technology 
Hooper, H. Elston, Ph.D., Chief, Field Operations Division 
Libman, Gerald, Chief, Program Development and Review Division 
Whorley, Mrs. Darlene R., Chief, Career Development Unit 
Keller, Andrew Z., D.M.D., Chief, Epidemiologic Studies Unit 

Health Services Research and Development Service 

Evans, Carleton C, M.D., Director, Health Services R&D Service 

Hayes, Edwin W., (Acting) Deputy Director, Health Services R&D Service 

Grovert, Miss Verna N., Professional Research Asst., Health Services R&D 

Service 
Hayes, Kenneth C, Associate Director, Direct Care Delivery R&D Staff 
Frank, Bernard, Associate Director, Health Care Support R&D Staff 
Kenworthy, Joseph E., Associate Director, Administration and Management 

System R&D Staff 

(xin) 



MEDICAL RESEARCH IN THE VETERANS' 
ADMINISTRATION 



HIGHLIGHTS OF VA RESEARCH ACCOMPLISHMENTS 
FISCAL YEAR 1975 

Introduction 

During- the past fiscal year, continued progress in medical research 
lias produced important findings which are discussed briefly below. 
The scientific developments, as presented here, are selections which 
form a composite of additions to the field of medical knowledge which 
provides hopeful clues to solutions of single ailments and groups of 
disorders. All the accomplishments noted in this section have appeared 
as published research papers or have been presented at scientific and 
professional meetings. 

It should not be assumed, however, that various studies mentioned 
in these highlights are of greater significance, specifically, than others 
which may not have been cited. 

Effective prognosis for survival of prostatic cancer patients 

To predict the survival of patients with prostatic cancer, physicians 
have relied heavily on the clinical stage of the disease when the patient 
arrives for treatment as well as the pattern revealed by the micro- 
scopic study of cell structure of the tissue involved. In addition, a 
normal electrocardiogram and no history of cardiovascular disease 
have been favorable indications. Otherwise, means for prognosis in 
these cases has been limited. 

Recently, the VA Cooperative Urologic Research Group reported on 
an additional aid for predicting survival of these patients. The study 
involved 750 patients in hospital and outpatient clinics at 21 VA facili- 
ties. Nonprotein-bound serum Cortisol (NPC), and total 17-hydroxy- 
corticosteroid (17-OHCS) levels were determined before and after 
treatment. In general, it was found that the lower the initial value of 
XPC and 17-OHCS, the greater the probability of survival during the 
first year of treatment. The levels of these steroids appeared to be a 
better prognostic indicator of survival in the first year than did the 
patient's age, treatment, or stage of the disease. 

Change in blood pressure after stopping treatment 

Studies by the VA Cooperative Study Group on Antihypertensive 
Agents have indicated that adequate control of blood pressure for a 
sustained period on medication could result in a permanent ..modifica- 
tion in a small number of cases. 

(l) 



A group of 86 male patients with established hypertension had been 
treated for two years or longer with an effectiveness indicated by an 
average diastolic pressure below 96 mm. Hg during the last year of 
treatment. Older persons and those whose blood pressures were at the 
lower end of the spectrum of "high" blood pressure at the time medica- 
tion started were most apt to remain with normal pressure after 
treatment stopped. 

Advances in lung cancer detection 

Investigators from the Pulmonary Disease Section, VA Hospital, 
East Orange, N.J. and the Solomon A. Berson Research Laboratory, 
VA Hospital, Bronx, X.Y., report that the production of adrenocor- 
ticotropic hormone (ACTH) — in a "Big-' form molecularly larger 
than the pituitary ACTH — in lung tumors is clincially useful as a 
biological marker in lung cancer. "Big ACTH" has no bioactivity and 
leads to no clinically detectable endocrine syndromes, such as Cushing's 
disease. 

The immunossay of "Big ACTH" is potentially useful in both di- 
agnosis and treatment of lung cancer — the most common cancer in 
males. Because of the great sensitivity of radioimmunoassay, surgery 
may be unnecessary to obtain diagnostic specimens. In this study, 
bronchial washings also contain "Big ACTH." 

The report further suggests that in cases in which lymph node or 
liver biopsy specimens are histologically positive for cancer, but the 
primary site of the tumor is unknown, the probability of the site being 
in the lung is favored if "Big ACTH" can be detected in the tissue. 

Breakthrough in diagnosis of breast cancer 

During a study of plasma membranes of cells from normal, can- 
cerous, and other abnormal human breast tissue, a San Francisco VA 
research biologist discovered alterations in the appearance of the 
plasma membrane of glandular epithelial cells lining the mammary 
ducts. Specimens of cancerous breasts (even from the supposedly nor- 
mal portions), or noncancerous abnormal breasts, could be distin- 
guished from normal. 

Normal epithelial cells have a plasma membrane that appears to have 
a multitude of minute, hair-like projections, known as microvilli, giv- 
ing the cells the appearance of brushes. Specimens from cancerous 
tissue show three distinct alterations of the microvilli, by which the 
investigators could easily distinguish the specimens of cancerous breast 
tissue from all other specimens. 

Coronary-risk screening 

In an attempt to arrest the development of the current high mortality 
in coronary heart disease, a VA cardiologist and colleagues began a 
long-term epidemiologic study sponsored by the Long Beach, Cali- 
fornia Heart Association. They screened 2,524 Long Beach citizens, 
mostly in their forties and fifties, with no history of heart disease. 
Six major risk factor's known to predispose people to coronary heart 
disease were evaluated. 



The investigators found that in many adults showing no symptoms, 
risk factors predisposing to coronary heart disease are not being de- 
tected or treated. They conclude that the best approach to the epidemic 
of coronary heart disease is prevention ; first, by detecting the presence 
of risk factors and then, by starting long-term treatment. 

Electrocardiogram analysis by computer 

From the VA Hospital, Washington, D.C., computer analyses of 
electrocardiograms (ECG's) were submitted to a diagnostic test 
against two of the nation's expert cardiologists. The result was cardi- 
ologists 61 percent correct, computer 88 percent correct. 

The computer has a precise memory of the profiles of many thou- 
sands of patients with known heart diseases. If a new record resembles 
a profile m the computer's memory, a diagnosis can be made. 

Independently, cardiologists at the VA Hospital, Minneapolis, Minn., 
tested the computer analyses in more than 1,000 cases and found it 
88 percent correct, a degree of reliability they judge sufficient to war- 
rant using the computer for ECG analysis on a routine basis. 

Pain following chest surgery alleviated by nerve-freezing 

Pain after chest surgery limits the ability of patients to breathe 
deeply and cough frequently enough to avoid pulmonary complications. 
Drugs given to relieve the pain often leave the patient with shallow- 
respiration and inadequate coughing reflex. 

To overcome these difficulties, a new technique called "cryoneurolysis* 7 
was carried out on 38 patients, with an equal number of controls, at 
two hospitals — the VA Hospital, Albuquerque, X.M. and the Roswell 
Park Memorial Institute. 

A significant decrease was found in the need for narcotic dosage 
during the postoperative period when cryoneurolysis was used. This 
process anesthetizes the incision and does not require repetition. The 
patients breathe deeply and cough normally during convalescence and 
are easily able to sit up and use the arm on the operated side, which 
greatly simplifies nursing care. 

National study of operating room hazards 

An investigator at the VA Hospital, Ann Arbor, Mich., was largely 
responsible for a national study by the American Society of Anesthesi- 
ologists (ASA) identifying risks to some hospital personnel. It found 
that breathing waste anesthetic gases in the operating room (OR) 
is hazardous to health and that OR personnel had a significantly 
higher incidence or cancer, kidney and liver disease, and abortion. Also, 
there was a far greater incidence of birth defects occurring among 
children of these health professionals than among professional people 
not working in operating rooms. 

The hazard, first noticed in Russia and European countries, was 
confirmed in the U.S. by studies of Michigan OR personnel by the VA 
investigator who brought it to the attention of the ASA. His prelimi- 
nary findings strongly suggest that the anesthetic gases are at least 
partly responsible for these hazards — particularly birth defects and 

70-799—76 2 



cancer. Several anesthetic gases are similar in chemical structure to 
known human carcinogens. The investigator strongly recommends 
venting waste anesthetic gases at all locations where anesthetics are 
given. 

Drug dependence research 

Exploring the possibility that different classes of psychoactive drugs 
exert different patterns of effects on sleep, medical investigators at the 
VA Hospital, San Francisco, Calif., studies the effects of a high dosage 
of tetrahydrocannabinol (THC) — considered to be the main ingredi- 
ent of marijuana — on the sleep patterns of young patients, average 
age '2~> years, who were accustomed to using marijuana. 

In the present study, administration and withdrawal of high dosages 
of THC induced striking changes in electroencephalogram (EEG) 
sleep patterns. These effects were far greater than those produced on 
waking EEG activity. 

The investigators suggest that THC, because of its apparently 
unique pattern of effects on sleep, could prove to be a useful tool in 
understanding the mechanisms and pharmacology of sleep. 

Infection surveillance reduces hazard in new hospital 

Monitoring of hospital-acquired infection at the VA Hospital. 
Hines, 111., led to the discovery of a near double increase of infections 
caused by bacteria in the blood of patients a few years ago. The find- 
ing was remarkable since it followed the relocation of patients to a 
new. 16-story hospital with all modern facilities. 

The epidemic was found to be caused by Pseudomonas aeruginosa 
and a number airborne fecal flora — organisms commonly encountered 
in the human alimentary tract and in sewage. Through scientific tests, 
including air sampling, the source was traced to a chute-hydropulping 
waste disposal system interlinking all 16 floors of the new building, 
which contaminated the air. When the faulty disposal system was 
closed and sealed off, and a new method of disposal introduced, the 
number of airborne infective agents returned to normal. The report 
urges hospital designers to prevent the described sources of gross con- 
tamination and serious hazards to the hospital environment. 

Pancreatitis treatment 

Aside from different treatment for the two kinds of pancreatitis — 
hemorrhagic and edematous — the outlook is grave for the hemorrhagic 
form which has a mortality rate of 30-50 percent or higher, compared 
to a mortality of 5-1 o percent observed in cases of edematous pan- 
creatitis. Thus, early determination whether a patient has acute, 
swollen pancreatitis or the more critical hemorrhagic form is crucial 
to both treatment and prediction of the probable course and outcome 
of the disease. 

Medical investigators at the A' A Hospital, Sepulveda, Calif., report 
lliat the detection of met hemalbninin in the blood scrum or effusion 
from the abdominal or cliest cavities of patients is virtually a certain 
indication of the hemorrhagic form of pancreatitis. They were able 
to make {he crucial determinat ion of (lie presence 1 or absence of me- 



themalbumin by means of a simple, quick spectre-photometric assay 
developed and reported by them earlier. 

Diabetes treatment 

Traditionally, the metabolic disorders of diabetes mellitus have been 
ascribed entirely to insulin deficiency. However, more recently, a re- 
search team at the VA Hospital, Dallas, Texas, has demonstrated two 
new lines of evidence supporting the theory that the opposing hormone, 
glucagon, is involved in the development of the severely high blood 
sugar levels that are typical of diabetes. 

The research group found that development of this abnormally high 
blood sugar level does indeed require the presence of glucagon. Finally, 
suppression of glucagon in animals with experimentally induced 
diabetes led to a rapid reduction of the high blood sugar level. This 
suggests a potentially valuable new approach to the treatment of 
diabetes. 

Danger of high doses of vitamin C 

In the course of treating nine Vietnam veterans at the VA Hospital. 
Bronx. X.Y., who were receiving ascorbic acid tablets (vitamin C) 
to maintain a urine acid level sufficient to help prevent infection, in- 
vestigators observed that four of the nine paraplegics had very low 
levels of serum vitamin B 12 — the antianemia factor of liver extract 
and the most potent antipernicious anemia substance known. 

Evaluating the reasons for this deficiency, the Bronx investigators 
discovered that large doses of vitamin C. such as those recently recom- 
mended for prevention of the common cold, may destroy from 50 to 90 
percent of the vitamin B 12 contained in a meal. 

Research in nuclear medicine 

Medical investigators at the VA Hospital. Lexington, Ky., have 
reported a new technique for the thyroid function test using the radio- 
isotope 99m Technetium-pertechnetate, which saves time and money 
while reducing the hazard of radiation exposure to the patient ? s 
thyroid gland by almost 10,000 times. 

The results of their technetium thyroid-scan study were so nearly 
identical to the standard 131 I-radioactive iodine uptake (RAIU) test, 
that the investigators recommended that their new radioisotope tech- 
nique be used in place of the 24-hour RAIU test in screening and 
diagnosing possible thyroid disease in the interest of saving time, 
money and radiation exposure. 

Research in speech pathology 

Speech pathologists have divided oral communication into two 
kinds — transmission of meaning and of emotion. The former relates 
to putting words together to convey an idea ; the latter, to altering in- 
flections or pitch of the voice to convey emotion. Xot only a persoms 
ability to convey information orally, "but his ability to understand 
persons speaking to him may be disturbed by damage to the brain, 
such as in aphasia resulting from a stroke. Aphasic patients who are 
unable to use speech to convey ideas have been found to be able to 



6 

recognize the emotion conveyed by a voice even though they do not 
understand the words. 

Investigators at the VA Hospital, Gainesville, Fla., recognizing an 
indication that the two kinds of speech comprehension are controlled 
by different areas of the brain, designed an experiment to determine 
if there are differences between the sides of the brain in the compre- 
hension of the emotional content of speech. 

The results suggest that aphasic patients with right-sided damage 
have a defect in comprehension of the emotional content of speech — 
medically referred to as auditory affective agnosia. 

A new technique in oral biology 

A medical investigator at the VA Hospital, West Haven, Conn., has 
made use of Scialom pins for setting fractures of facial bones which 
cannot be managed by splints. The pins bear the name of the French 
dentist who designed them originally for securing dental crowns. They 
are made of tantalum, a noncorrosive material used in transplanta- 
tions, and range from one to two inches long and are similar to a 
hypodermic needle in diameter. 

A single pin is relatively easy to insert into the bone surrounding 
the tooth socket. Since it does not adhere to the bone, but actually 
becomes loose in a short time, the pin can be withdrawn easily by the 
dentist after a few days. When the investigators fused togetner a 
double tripod of pins with three prongs extending into the lower jaw- 
bone and the opposite three embedded in the crown, the tri-plant was 
almost impossible to dislodge. The successful use of this procedure 
with animals and clinical results with four accident victims was re- 
ported this past year. 

CONFERENCE ON VA STUDIES IN MENTAL HEALTH AND 
BEHAVIORAL SCIENCES 

More than 600 registrants attended the 20th Annual Conference on 
VA Studies in Mental Health and Behavioral Sciences, April 9-11, in 
Chicago, 111. One of the main features of the program was an invited 
address by Marat Vartanian, Chief of the Laboratory of Pathophysi- 
ology at the Institute of Psychiatry of the Academy of Medical 
Sciences in the Soviet Union, Moscow, who discussed biological studies 
of endogenous psychoses in the Soviet Union. 

The keynote address was delivered by Dr. Neal Miller of The Rocke- 
feller University, New York, on applications of learning and biofeed- 
back to medicine and psychiatry. Reports on the current status of six 
VA Cooperative Studies included research on methadone, drugs and 
sleep, and recovery from aphasia. In addition to several symposiums 
concerning drug abuse, sexuality, mental health care and therapeutic 
developments, 12 teaching seminars were held in areas ranging from 
prescribing psychotherapeutic drugs, death and dying, to evaluative 
studies in treatment and prevention of suicide. 

VA PARTICIPATES IN PSYCHIATRIC MEETING 

One of the highlights of the 128th Annual Meeting of the American 
Psychiatric Association, Anaheim, Calif., May 5-i>, was an all-VA 



panel on "A View of Psychiatry in Moscow and Leningrad.'' More 
than 25 VA physicians and researchers either presented scientific 
papers, contributed to panel discussions, were moderators and/or pre- 
sided as chairman of scientific sessions. Of particular note was a session 
on lithium in depression ; a paper on treatment-related factors in alco- 
holic populations; and a session on drugs of abuse in which VA pre- 
sented findings in research on EEG Sleep Patterns and Drug Abuse. 
Walter E. Barton, M.D., VA Hospital White River Junction, Vt., 
and former Medical Director of the APA, receive the Distinguished 
Service Award. The Bronze Medal was awarded for a VA exhibit on 
"A Computer- Assisted Psychiatric Assessment Unit," and a scientific 
paper was presented describing this innovative approach to ps} T chi- 
atric decision-making. 

SEVERAL VA SYMPOSIUMS HIGHLIGHT PSYCHOLOGICAL 

MEETING 

One of the highlights of the 82nd Annual Meeting of the American 
Psychological Association, New Orleans, August 30-September 3, was 
a symposium sponsored by VA and the Division of Psychologists in 
Public Service, on ''Coming of Age in the Delivery of Mental Health 
Services." 

An all-VA symposium focused on "Impact on Patients of Transi- 
tions in Health Services" and a number of other symposiums, round 
table discussions, workshops and invited panels in which VA psycholo- 
gists participated included such areas as : problems of older people ; the 
aging woman; new directions in treatment and rehabilitation of head 
injury; cardiac considerations in rehabilitation: recent approaches to 
brain-language relationships; biofeedback phenomena; psychological 
functions in epilepsy research; treatment and research with drug 
users; and studies of brain-damage and schizophrenia. A VA exhibit 
presented the variety of professions necessary to maintain the VA 
hospital system. It contained an invitation to clinical and counseling 
psychologists and career professionals. 

VA SPONSORS MEDICAL RESEARCH MEETING 

To ensure a better understanding of the responsibilities of Medical 
Research Advisor}- Groups and their relation to each other, a combined 
meeting of these groups and Central Office personnel was held June 
3-4, at the Sheraton National Hotel. Arlington. Va. This meeting, the 
first of its kind, was attended by members of the Program Research 
Advisory Group (PR AG), the Regional Research Advisory Groups 
(RAG), the Research Advisory Committee (RAC), and a number 
of Research Program Specialists. 

The agenda included presentations by the Assistant Chief Medical 
Director for Research and Development; the Director, Medical Re- 
search Service; other VACO staff and selected Research Program 
Specialists who described the state of VA research in their specialty 
areas. In addition, two panel discussions were held; one on the 
Regional Research Advisory Groups, the other on the activities of the 
Research Program Specialists. 



NATIONAL AND INTERNATIONAL AWARDS 

During the fiscal year, four VA researchers received recognition on 
a national or international scale: Dr. Ludwik Gross, VA Hospital, 
Bronx, N.Y. ; Dr. Roger Unger, VA Hospital, Dallas, Texas; Dr. 
Hubert Pipberger, VA Hospital, Washington. D.C. ; and Dr. William 
Oldendorf, VA Hospital (Brentwood), Los Angeles, California. 

The Albert Lasker Basic Medical Research Award was presented to 
Dr. Gross for his discovery that viruses induce, or cause, leukemia and 
cancer in mammals and for his continuing work in the biology and 
epidemiology of these viruses. His work stood alone for many years, 
yet today it is the basis of the major thrust in cancer research funded 
hy the National Cancer Institute. 

Dr. Unger's work has been recognized not once but twice. He re- 
ceived the Banting Medal of the American Diabetes Association and 
the David Rumbough, Jr. Award of the Juvenile Diabetes Founda- 
tion. The research which prompted these awards has shown that the 
body's blood sugar balance is maintained by two hormones — insulin, 
with a role which has been known for years, and glucagons, whose 
exactly opposite role was not appreciated. Dr. Unger's work is revo- 
lutionizing the understanding of diabetes and may lead to drastic 
changes in its treatment. 

Dr. Pipberger pioneered in the computer interpretation of electro- 
cardiograms — heart tracings. His very sophisticated technique is 
already used in examining patients. For his work, he received the 
Einthoven Medal from the University of Leiden. Holland. 

Dr. Oldendorf received the first Ziedes des Plantes Medal from the 
Medical Physics Society of Wurzberg, West Germany. Although he 
is a neurologist, Dr. Oldendorf originated an X-ray technique for 
scanning the brain. Called "transmission section" scanning, his concept 
is the basis for current computerized methods used for diagnosis. 

WILLIAM S. MIDDLETON AWARD 

The 1974 William S. Middleton Award. VA's highest honor for 
medical research, was presented to Paul A. Srere. Ph. D., Chief of the 
Preclinical Science Unit, VA Hospital, Dallas, Texas, and Professor 
of Biochemistry, University of Texas Southwestern Medical School. 
1 )r. Srere was recognized for his outstanding accomplishments over 1 he 
past 20 years and. particularly, for his research in the areas of protein 
chemistry, enzymology and cell biology conducted at the Dallas VA 
Hospital during the past 8 years. These included notable biochemical 
discoveries in key cellular metabolic pathways regulating lipid and 
carbohydrate synthesis and storage. 

The award, named for the late Dr. William S. Middleton, famous 
clinician, educator, and VA Chief Medical Director from 1955-65, has 
been given each year since its inception in 1960. Dr. Middleton died 
September 9, 1075. 

The first of these awards was given to the late Solomon A. Berson, 
M.I).. Chief, Radiosotope Service and Senior Medical Investigator. 
and Rosalyn Yalow, Ph. I).. Chief, Nuclear Medicine Service and 
Senior Medical Investigator at the Bronx VA Hospital, New York 



City. They developed the technique of radioimmunoassay, an invalua- 
ble tool for detecting and measuring tiny amounts of biological sub- 
stances. This has revolutionized the science of endocrinology. Since 
then the recipients have been : 

19G1: Hubert A. Pipberger. M.D.. Chief. VA Research Center for 
Cardiovascular Data Processing, Washington, D.C. VA Hos- 
pital, who pioneered in computer interpretation of electro- 
cardiograms. 

1962 : Leslie Zieve, M.D. and William C. Vogel, Biochemist. Min- 
neapolis VA Hospital, for studies of phospholipids, and 
phospholipases. 

1963 : Stanley Ulick, M.D., Bronx VA Hospital, for his discoveries in 
the chemistry and metabolism of mineral corticoid hormones. 

1964: Robert O. Becker, M.D., Chief, Orthopedic Section, Syracuse 
VA Hospital, for demonstrating that an electrical control sys- 
tem can be used to stimulate the regeneration of tissue in 
mammals. 

1965: Lucien B. Guze, M.D. and George M. Kalmanson, M.D., Los 
Angeles VA Center, for discerning the host-parasite relation- 
ship in chronic, infectious kidney disease. 

1966 : Leo A. Hollister, M.D., Palo Alto VA Hospital, for numerous 
significant contributions in the field of therapeutic drugs for 
mental illness. 

1967 : Leonard T. Skeggs, Ph.D., Biochemist, Cleveland VA Hospital, 
for automated laboratory test devices and biochemistry of 
hvpertension. 

1968 : Thomas E. Starzl, M.D., Chief, Surgical Service, Denver VA 
Hosiptal, for pioneering surgical transplantations of 
kidneys and livers, and the development of antilymphocyte 
globulin and other immunosupxHessants to suppress the re- 
jection of transplanted organs. 

1969: Roger H. Unger, M.D., Associate Chief of Staff, Dallas VA 
Hospital, for his conception of the physiology of metabolism 
of fats and carbohydrates, basic to better therapy for diabetes 
patients. 

1970: Andrew V. Schally, Ph.D.. Chief, Endocrine and Polypeptide 
Laboratories, VA Hospital, Xew Orleans. La., for his in- 
vestigations of the physiology and biochemistry of hy- 
pothalamic neurohormones. 

1971: Marcus A. Rothschild, M.D.. Chief, Xuclear Medicine. VA 
Hospital. New York City, for research in liver disease con- 
trol mechanisms affecting serum albumin, and the patho- 
physiologic regulation of liver metabolism. 

1972 : Kenneth Sterling. M.D., Chief of the Protein Research Labora- 
tory VA Hospital. Bronx, X.Y.. for his outstanding accom- 
plishments in hematological and endocrinological research 
usinc: the techniques of nuclear medicine. 

1973 : Ludwik Gross, M.D., Senior Medical Investigator and Chief, 
Cancer Research Unit, VA Hospital, Bronx. X. Y., for out- 
standing accomplishments in oncogenic virus research. 



10 

THE VA MEDICAL RESEARCH PROGRAM 

An abbreviated history 

Medical research was first incorporated officially into the basic mis- 
sion of the Veterans Administration's medical care program on 
September 2, 1958, when the Congress enacted Public Law 85-857, 
which so amended Title 38 of the U.S. Code that Section 4101 would 
henceforth read : u . . . The functions of the Department of Medicine 
and Surgery shall be those necessary for a complete medical and 
hospital service, including medical research." 

Medical research was a very modest program in the VA at the end 
of World War II. Such medical research as existed at that time was 
almost entirely conducted by contracts with members of medical 
schools which were affilated with the VA. When the Congress made its 
first appropriation of VA funds earmarked for medical research in 
fiscal year 1955, the total research funding was a mere $4.8 million. 

Greater promise seemed to lie in intramural research programs 
which were augmenting the medical research contract program, and 
in 1956 the contract program was entirely supplanted by intramural 
research projects. That first year in which the VA directed its medical 
research, individual research investigators reported on 3,644 research 
projects, and made enough progress to have 900 reports published in 
professional and scientific journals. 

The early VA medical investigators were quick to discover and put 
to the test one of their most valuable assets — the cooperative study. 
In a cooperative study, investigators from, any number of different VA 
facilities may agree to study a selected problem under uniform guide- 
lines. The unique quality of VA cooperative studies is that the in- 
vestigators may rapidly amass significant statistics by drawing upon 
the largest patient population available to any single agency in the 
Western World. 

One of the earliest of these cooperative studies was initiated in 1946 
in cooperation with the Armed Forces, to study the effectiveness of the 
chemotherapy for tuburculosis. The success of this study in deter- 
mining the optimum medical treatment, caused the management of 
that disease to become so effective that the VA was able to close or con- 
vert all of its tuberculosis hospitals to general medical and surgical 
care. The cooperat ive study scored another major success in finding the 
most effective chemotherapy for treating neuropsvchiatric patients 
which threatened to tax the VA neuropsvchiatric (NP) hospitals be- 
yond their capacity after the end of World War IT. The success of this 
study enabled the VA to care for the NP patients in existing facilities 
at. a time when it had been thought that the number of NP hosoitals 
would have to be doubled at a cost estimate approaching a billion 
dollars. 

The classic VA cooperative study on the benefits of treating mild 
hypertensive patients with antihypertensive medicine established the 
Vftlue of early treatment of hicfh blood pressure in prolonging active, 
useful life and comfort in the Nation's aging population. Earlier 
findings showed that the risk of crippling or fatal strokes is directly 



11 

related to the height of a person's blood pressure, and that proper 
treatment now available will reduce the risk of having a stroke by 75 
percent. This cooperative study is largely responsible for a National 
and probably world-wide mobilization of health care resources to find 
and treat effectively those persons who are developing even mild high 
blood pressure. 

Medical research in VA facilities increased steadily in range and in 
accomplishments from the time it first became part of the total pro- 
gram of medical care for veterans. Since 1955, the Congress has made 
the following annual appropriations for medical research in the VA : 

1957 $10,000,000 1967 $42,911,000 

1958 10, 344, 000 19GS 44, 472, 000 

1869 15,344,000 1969 46,616.000 

1900 17,344,000 1970 57, 134, 000 

1961 21,500,000 1971 60,686.000 

1962 27, 000, 000 1972 67, 790, 000 

1963 29.500,000 1973 74.702,000 

1964 32,572,000 1974 72,876,000 

1965 36, 50S, 000 1975 87, 66: J >. OOi » 

1966 39,983,000 1976 87,722. 000 

MEDICAL RESEARCH ADVISORY COMMITTEES 

Merit Review Boards. — In fiscal year 1975, components of local 
hospitals' institutional research programs continued to be centrally 
reviewed by fifteen categorical Merit Review Boards. This process for 
establishing the scientific merit of major component programs formed 
a necessary part of local and National institutional program review 
and provided each hospital with a uniform basis for judging the quality 
of its programs and investigators for the most efficacious distribution 
of research funds. The extensive research program critiques and sum- 
mary statements returned to hospitals provide an essential management 
tool for decentralized administration and are of value in central plan- 
ning for research construction and analysis of need for research equip- 
ment and facilities and research staffing requirements. The support of a 
quality research milieu at the local level has served to support the 
patient care mandate of the VA and to recruit and retain quality clin- 
ical staff. 

The Medical Research Career Development Committee (Consult- 
ant). — Comprised of non-VA medical and education specialists, acts 
as the selecting body for the positions of research associates, psychol- 
ogy research associates, clinical investigators, medical investigators, 
and senior medical investigators. In addition, the group makes the 
final recommendation on the William S. Middleton Award. 

The Cooperative Studies Evaluation Committee. — Comprised of 
selected experts in the field of medical collaborative research, mostly 
research physicians with varying specialty backgrounds (phychiatry, 
surgery, internal medicine, etc.) and medical biostatisticians. It pro- 
vides informed scientific evaluation of all cooperative studies as to 
their merit and validity, as well as professional evaluation of their 
relevance and importance to medicine and medical science. 

(Note. — A listing of the above Board members and Committee 
members appears in Part II, Data Supplement.) 



12 

ADMINISTRATIVE DATA 

The fiscal year 1975 Congressional appropriation for medical re- 
search in the' Veterans Administration was $87,663,000. The amount 
of $1,167,000 was brought forward from the 1974 appropriation and 
estimated reimbursements of $4,540,000 increased the total available 
for the year to $93,370,000. Total program costs for the fiscal year 
were $91,627,000 including actual costs subject to appropriation reim- 
bursements earned or received totalling $4,597,000. The distribution 
of total costs by research activity for the year was : 

Institutional Research : 

Administration $6, 161, 000 

Common research support 5, 522, 000 

Biomedical research projects 39, 011, 000 

Other professional research 6, 969, 000 

Animal research facilities 5, 429, 000 

Special Research : 

Special laboratories or programs 856, 000 

Cooperative studies 6, 752, 000 

Career development program 9, 026, 000 

Other designated research 1, 155, 000 

Minor alterations and improvements 875, 000 

Equipment : 

Construction projects 559, 000 

All other 9, 311, 000 

Total costs 91, 627, 000 

MEDICAL RESEARCH CAREER DEVELOPMENT PROGRAM 

Through the Career Development Program the VA is able to at- 
tract and retain potential and experienced physician investigators. The 
physicians, dentists, and medical scientists in the program benefit in 
that they may systematically progress along avenues of their choice 
in research and clinical careers. Further the Career Development Pro- 
gram operates to the mutual advantage of the VA and affiliated uni- 
versities by promoting intellectual cross-fertilization and by achieving 
optimal utilization of the facilities and educational resources of both 
institutions. 

The spectrum of the career development program includes four 
levels; the senior medical investigator position is at the top, and is 
open to outstanding VA investigators of proven achievement who are 
expected to continue with excellence in research. The next rung of the 
career progression ladder is that of medical investigator, which pro- 
vides an opportunity for physicians and dentists who have established 
themselves as successful investigators to pursue research and clinical 
activities in a targeted area of concern. The clinical investigator level 
is designed to encourage talented young investigators with an aptitude 
tor research to supplement their medical knowledge and skill with an 
equal competence in the sciences and technology. The research asso- 
ciate level is designed for physicians and dentists who have demon- 
strated all interest and aptitude in research and wish to combine this 
with clinical skills. 

Senior medical investigator program 

The senior medical investigator program was initiated in January 
11)5!). This program is designed to give recognition to senior physi- 



13 

cians and dentists who ha\~e distinguished themselves in research in 
the Veterans Administration and who give promise of continued pro- 
ductivity in research. These senior investigators are permitted to work 
independently on research of their own choosing. They may accept 
teaching and patient care responsibilities, but the primary focus is on 
their research activities and they are supported directly from research 
funds. Eleven distinguished investigators have been singled out for 
this appointment. Dr. Samuel H. Bassett, VA Center Los Angeles, 
California (deceased) ; Dr. Solomon A Berson, VA Hospital, Bronx, 
X.Y. (deceased) ; Dr. Oscar Auerbach. VA Hospital, East Orange, 
X.J. : Dr. Edward D. Freis. VA Hospital. Washington, D.C. ; Dr. Lud- 
wik Gross, VA Hospital, Bronx, X.Y. ; Dr. Morton I. Grossman. VA 
Center, Los Angeles. Calif. : Dr. Paul Heller. VA Hospital, Chicago 
(WS), 111. ; Dr. Jay T. Shurley. VA Hospital, Oklahoma City, Okla. ; 
Dr. Rosalyn Yalow, VA Hospital, Bronx, X.Y. ; Dr. Sidney H. Ingbar, 
VA Hospital, San Francisco, Calif. : and Dr. Andrew V. Schally. VA 
Hospital, Xew Orleans, La. Each holds a professorship in his or her 
specialty with the affiliated medical school. 

The findings of Dr. Auerbaclvs research on smoking and lung cancer 
are well known. More recently he has focused on emphysema and car- 
diovascular sequelae found after long-term cigarette smoking in 
animals and man. 

Dr. Edward Freis is widely known for outstanding research on hy- 
pertension. Among many other activities. Dr. Freis is chairman of the 
VA's 16-hospital cooperative study of antihypertensive agents. 

Dr. Ludwik Gross, a pioneer of modern research on the virus origin 
of cancer, is internationally known for his finding of cell-free trans- 
mission of leukemia in mice, the isolation and identfication of the 
mouse leukemia and the parotid tumor viruses. Dr. Gross was honored 
in 1975 by the Cancer Research Institute for his contributions to the 
field of cancer immunology. In 197-i, he received the Albert Lasker 
Basic Medical Research Award. 

Dr. Morton I. Grossman's major research activities have been in the 
fields of gastric and pancreatic physiology and the regulation of hun- 
ger and appetite. His current research is on the interaction of nervous 
and hormonal factors in the regulation of gastric and pancreatic 
secretion. 

Dr. Paul Heller has distinguished himself by his research in disease 
of the blood, especially with reference to abnormal hemoglobins (such 
as seen in sickle disease) and in blood protein disorders. He heads the 
VA's 13-hospital cooperative study of sickle cell disease. 

Dr. Andrew V. Schally is known for his accomplishments in isolat- 
ing, determining the structure of, and synthesizing neurohormones of 
the hypothalamus, particularly thyrotropin releasing hormone (TRH) 
and leuteinizing hormone releasing hormone (LH-RH), all of which 
played a leading role in opening an entirely new and important field 
in neuroendocrinology. Follicle stimulating hormone-releasing hor- 
mone (FSH-RH) activity seems to be an intrinsic part of the LH- 
RH molecule. 

Dr. Jay T. Shiirley's research is on the nature of the brain-mind 
adaption of the individual to drastically altered or stressful environ- 
ments. The preception and processing of information in man and the 
psychoplwsiology of sleep disorders and of sensory and perceptual 
isolation are two specific lines of investigation currently in progress. 



14 

Rosalyn S. Yalow, Ph.D. was the first non-physician to be appointed 
a senior medical investigator. Dr. Yalow's major research activities 
include radioactive labeling of biological compounds, radioimmunoas- 
say of various hormones, metabolism of labeled biologicals, and 
related topics. In 1975 Dr. Yalow was elected to membership in the 
National Academy of Sciences. 

Dr. Sidney H. Ingbar resigned as Senior Medical Investigator dur- 
ing fiscal 1975 to return to Harvard Medical School. 

Medical investigator program 

This program provides established successful investigators an op- 
portunity to pursue research activities for a major portion of their 
time with the remaining time spent in teaching and patient care. Can- 
didates selected will be those from whom the VA can anticipate con- 
tinued productivity; they receive 6-year appointments. 

A list of the scientists who served as medical investi gators during 
fiscal year 1975, along with their hospitals and disciplines appears in 
Part II, Data Supplement. 

Clinical investigator program 

The Clinical Investigator Program is designed to provide a three 
year concentrated research experience for maturing physicians and 
psychologists. 

The candidates for clinical investigator program are chosen from 
medical graduates and clinical psychologists who have extended their 
education by means of residency or similar programs. Successful candi- 
dates have also revealed an ability for significant research by post- 
doctoral research fellowship and additional research experience. 

The names of the clinical investigators during fiscal vear 1975, their 
hospitals and disciplines appear in Part II, Data Supplement. 

Research associate program 

The research associate program is principally designed to prepare 
physicians and clinical psychologists to bring advanced skills to bear 
on problems of particular importance in the care of veteran patients. 
Under the guidance of qualified preceptors the associates are encour- 
aged to learn new technologies at their hospitals. 

A list of those Research Associates who served, along with their 
hospitals and specialties, appears in Part II, Data Supplement. 

Psychology research associates 

The VA research associate program began as one for psychologists 
to enter careers as responsible investigators and soon developed to 
include many medical specialties. The psychology portion of the pro- 
gram continues today as a research experience for psychologists who 
evidence strong potential for research. There is broad opportunity 
for selection of the area of research interest and association with pi-e- 
ceptors of acknowledged achievement and stature in the scientific com- 



15 

munity, laboratories engaged in psychophysiological, experimental, 
clinical, or social psychological research. 

In fiscal year 1975, there was one psychology research associate in 
training. This is the last one who will be designated as psychology re- 
search associate. This portion of the program is being totally integrated 
into the Research Associate Program. 

Advanced specialty training program 

The clinical associate position was initiated in fiscal year 1968 in 
Advanced Specialty Training Programs. These training programs pro- 
vide an initial clinical and research assignment of high quality spe- 
cialty training for physicians and dentists who had completed two 
years on an approved residency or its equivalent. These programs are 
currently being phased out. A list of training programs and facilities 
appears in Part II, Data Supplement. 

RESEARCH PROGRAM 

The research program is designed to meet three major obligations. 
The first of these is to provide the best care for veterans. In meeting 
this need the research program has been used as a device to recruit 
physicians and other scientists. Since these individuals come largely 
from the academic world, such recruitment is heavily dependent upon 
the opportunity to conduct clinical research in a hospital setting. These 
research efforts, always highly individualized, must be integrated into 
a total research program which is balanced, particularly with refer- 
ence to the patient population we serve. It would be impossible to do 
more than summarize the major thrust here. However, the clinical 
research summaries which follow will give some idea of the clinical 
care orientation and broad range of interest of our physicians. 

It is also clear that the second responsibility, mainly that of pro- 
viding our fair share of biomedical research effort for the good of the 
entire country, is being met consonant with the resources made avail- 
able to us. 

A final and very important obligation is to utilize the unique capa- 
bility of the YA hospital system in answering questions which can 
only be answered by large numbers of patients under a single manage- 
ment. This capability is unique to the YA in this country and, when 
one considers that the number of patients treated exceeds that of some 
countries with nationalized systems, it is not surprising that our multi- 
hospital studies have received international attention. These are also 
summarized below. 

HEALTH SERVICES RESEARCH AND DEVELOPMENT 

The Health Service Research and Development Servie (HSR&DS) 
has continued to place emphasis on developing a program keyed to the 
most comprehensive and expeditious delivery of health care to patients 
in the YA system. During the year this program was restated in 
terms of the goals and objectives established by the Department of 
Medicine and Surgery (DM&S) management by objectives process, 



16 

thereby insuring integration of research and development plans with 
operating plans. 

The development of criteria for the quality of care and of instru- 
ments to measure the degree of quality attained is a primary DM&S 
and HSR&DS goal. Sets of instructions, guidelines and instruments 
developed to assist in evaluating the quality of medical/surgical and 
mental care were issued during the year and distributed throughout 
the VA system to aid the hospitals in developing their individual sys- 
tematic internal review programs for self-evaluation as part of the 
Health Services Review Organization (HSRO) program. On-going 
work includes refinement of existing HSRO tools and methodologies 
and the development of new ones for application in areas not yet 
adequately covered. Also, plans for the evaluation of the impact of 
HSRO are being developed, looking toward evaluation and revision of 
HSRO in a continuing program of improvement. 

With the rapidly expanding demands for ambulatory care, a num- 
ber of projects have been supported that look to appropriate and effi- 
cient patient treatment prior to, or in lieu of, hospital admission. These 
projects often take the form of development, pilot test and evaluation 
of innovative health care delivery models. Modeling activities have in- 
cluded projects such as the prototype Preadmission Psychiatric 
Assessment Unit developed at the VA Hospital, Salt Lake City, Utah 
for evaluating the physical, psychological and social status of appli- 
cants for mental health care prior to their admission to or treatment 
at the hospital. 

This system for collecting data on, and assessing the condtion of, 
patients proved successful and was incorporated into the regular op- 
eration of the hospital at the completion of its pilot stage this year. 
A formal cost and effectiveness evaluation is now being conducted to 
determine the "exportability" of the model to other hospitals. 

Similarly, a project begun last year to develop and test clinical 
algorithms for diagnosis and treatment of simple acute illnesses will 
lead next year to pilot testing of the algorithms as an integral com- 
ponent of a functional ambulatory care model at the VA Hospital, 
Turson, Arizona, and possibly at other hospitals. 

In the area of hospital functions and services supporting direct 
patient care, recent studies include such varied subjects as cost-benefit 
analysis of manual and computerized patient appointment scheduling 
systems; pilot test of a semiautomated system for preparation of 
radiology reports; and initial development of a nation-wide on-line 
pharmacy information system that can provide patient medication 
history as well as the usual pharmacy inventory and control functions. 

Work on the planned integrated clinical and administrative hos- 
pital information system began with the initial steps to identify and 
define the fundamental data elements required in the operation and 
management of medical disl rids and their component hospitals under 
the regionalization concept now being implemented. 

The VA is cooperating with the National Center for Health Serv- 
ices Research of the Department of Health, Education and Welfare 
m two programs intended to encourage research and development in 
health services and to train personnel appropriately for such work. 
The National Center for Health Services Research will fund a number 



17 

of grants for the establishment of Health Services Research Centers 
in academic institutions having working relationships with health 
service delivery settings. 

To encourage VA hospital participation. HSR&DS has offered, to 
each VA health care facility that successfully participates with a uni- 
versity in applying for and obtaining a Health Services Research 
Center grant, funding to provide manpower for active participation 
by the hospital. Similarly, Education Service and HSR&DS have 
entered into a cooperative arrangement with the National Center to 
help provide interdisciplinary education and training in health serv- 
ices research to selected trainees. Each trainee will be expected to 
have a health care background and to be working for a Ph.D. in an 
approved educational institution. Those students who successfully 
complete the program will be offered VA employment in a variety 
of suitable positions through which they may be able to influence 
favorably VA health care delivery. 

PROSTHETICS RESEARCH 

The Prosthetics Research Study, Seattle, Washington, tested a con- 
trolled environment treatment developed in England. This treatment 
is intended to expedite healing of freshly amputated limbs. Though 
it does not allow immediate prosthetic fitting and ambulation, replace- 
ment by a rigid socket and intermediate prosthesis is possible after 
10 days. 

The VA Prosthetics Center, New York, X.Y., has developed a 
m}'oelectrically controlled electric hook capable of unusually high 
grasping force. Several prototypes are under evaluation. 

Cooperative studies were conducted involving possible prevention 
of amputation for peripheral vascular disease or at least amputation 
as distally as medically feasible. The Seattle Study, operating at the 
VA and other hospitals, and the VA Hospitals at San Francisco, 
Calif., and Castle Point, N.Y., have found increasing success in heal- 
ing after amputating not only below the knee but often at the ankle, 
in contrast to many texts which teach amputation through the thigh. 
Patients with more distal amputations, treated by immediate post- 
surgical prosthetics management, are more rapidly rehabilitated and 
discharged. Even the prosthesis costs substantially less than an above- 
knee artificial limb. 

Experimental prototypes of a unique combination power bed- wheel- 
chair were demonstrated during the year. They allow a quadriplegic 
independent mobility within a hospital or a ranch-style home and 
patio. 

Several ambulators are being designed to enable a patient who can- 
not stand independently to work in the upright position and to move 
voluntarily for short distances on level surfaces. These will allow 
activities in a kitchen, bathroom, office, or at a public telephone, espe- 
cially where narrow passages limit a wheelchair. 

Clinical studies on mobility and reading aids for the blind and par- 
tially sighted continued at the three Blind Rehabilitation Centers. 
Western Michigan University, with VA education funds, conducted a 
series of courses for orientation and mobility instructors on two ultra- 



18 

sonic aids and on the VA-supported laser cane. This new p??ol of skilled 
instructors will expedite transition from evaluation to wider clinical 
use by blinded veterans and others. 

CLINICAL RESEARCH 

Aging 

The Veterans Administration has recognized the importance of re- 
search on the varied aspects of aging by establishing Geriatric Re- 
search, Educational, and Clinical Centers. These new Centers embrace 
research in basic and in clinical areas. Investigations on the problems 
of aging are conducted also at other VA health care facilities; some 
dealing with medical and psychiatric conditions in aged persons are 
summarized under other headings. 

In a longitudinal interdisciplinary study of normal aging conducted 
at the VA Outpatient Clinic (OPC), Boston, Mass., a composite index 
of functional aging was developed. It was based on a dozen biological 
and behavioral measures which together accounted for about 65 per- 
cent of the variability in chronological age of more than 900 men aged 
20-83 years. Recent information from the same study indicates that 
the value of such functional measures, designed to predict both rates 
and stages of aging, probably will be limited to narrow age ranges. 
Different systems age at different rates and most do not change uni- 
formly across the adult age range. For example, the preferred age of 
retirement stays relatively constant until age 50 after which it shows 
a substantial increase. In contrast, pulmonary function declines at an 
increasingly slower rate with old age. In some older groups, pulmo- 
nary function even increases slightly over ten years, due to changes 
in smoking and exercise habits. 

Medical data, information on life style, personality and other be- 
havioral characteristics are available for participants in the Boston 
OPC Normative Aging Study, making it possible to identify several 
factors which modify patterns of aging. For example, the effects of 
smoking on pulmonary function, in comparison to those of age are 
quite small and remain about the same across the adult age range. 

Other information relating weight loss and smoking in the same 
volunteers indicates that almost 40 percent of the men who quit smok- 
ing do not incur' long-term weight gains. The data suggest that the 
frequently reported finding of weight gain following the cessation 
of smoking fails to take into account normal weight changes. 

It has been possible to employ measures of three dimensions of 
personality: anxiety-adjustment, introversion-extroversion, and open- 
ness to experience' to identify various reasons for smoking and to 
study the relation between anxiety and cognitive functioning in sev- 
eral age groups. . 

At the VA Hospital, Topeka, Kansas patients with diffuse brain 
damage and normal controls in two age groups were administered a 
Large battery of menial tests. In the older group the performance dif- 
fered as much between the normal and brain-damage subjects as it did 
in (he younger group, contradicting the hypothesis that the effects of 
aging on cognitive functioning resemble those of brain damage. 



19 

Functioning of the nervous system may decrease with age because 
the delivery of oxygen to the cells is deficient or because they cannot 
use oxygen efficiently. This hypothesis is the basis for the experimental 
use of hyperbaric oxygen therapy at the VA Hospital, Buffalo, X.Y. 
An investigator at the VA Center (Wadsworth) Los Angeles, Calif., 
working in collaboration with a Navy scientist, found that this tech- 
nique improved short-term memory and visual organization in sub- 
jects who scored poorly on the TTechsler memory scale. Although these 
results are encouraging for both practice and theory, fully-controlled 
studies of the relationship between cognitive functioning and oxygen 
therapy are lacking. 

Investigators at VA Center (Brentwood) Los Angeles, Calif., have 
confirmed the existence of age differences in chromosome abnormalities 
in cultured leukocytes. More were found in cells from elderly women 
than in those from young and middle aged adults. 

At the Oklahoma City VA Hospital, patients with senile dementia 
associated with atheroclerosis were given sufficient zinc sulphate to 
raise the average plasma zinc concentration by about 80 percent over 
a 24~week period. Compared to untreated controls, the patients showed 
no significant differences in physiological functioning, blood chem- 
istry, electroencephalograms or behavioral measures. Zinc sulphate 
administration did not improve cerebral functioning. 

Senile dementia with ataxia and incontinence can be due to normal 
pressure hydrocephalus, an unusually large accumulation of fluid in 
the cranium. VA clinical researchers at Boston and Minneapolis are 
engaged in evaluating surgical procedures for correcting this 
abnormality. 

Normal age differences in memory and cognitive processes continue 
to receive attention from VA scientists. At the VA Hospital, Syracuse, 
X.Y., retention for short lists of digits was superior when they were 
presented auditorily rather than visually; the opposite was true for 
prose. The modality effects were the same for young and old subjects. 

Two lines of research at the Boston OPC indicate that age dif- 
ferences in very long-term memory are quite small. In one study, reten- 
tion for pictures viewed under standard conditions was assessed im- 
mediately after viewing the pictures and again after intervals ranging 
from 4 weeks to '2y 2 years. Retention declined at about the same rate 
for all subjects and remained above a chance level after the longest 
interval. In the other study, no age deficits were found in the retention 
of popular information associated with earlier events, personalities 
and sayings. 

Age differences in the metabolism of the circulatory system were 
studied at the VA Hospital, Seattle, Wash, using tissue cultures of 
smooth muscle from the arterial wall. The uptake of lipoproteins in 
cultured cells did not change with the age of the donor. However, 
attempts to stimulate the growth failed when cells were relatively old 
in cultured life. The research suggests that the gradual accretion of 
lipids in the smooth muscle cells is a normal phenomenon. In other 
research, the investigators are comparing the lipid uptake of normal 
and diabetic patients to evaluate the hypothesis that the effect of 
diabetes is functionally equivalent to that of normal aging. 

At the VA Hospital, San Francisco. Calif., the morphological struc- 
ture of the livers of virgin male rats was compared to that of retired 

70-799—76 3 



20 

breeder rats with hyperlipidemia, arteriosclerosis and a shortened life 
span. 

The livers of older rats had a greater relative volume of lysosomes 
and the parenchymal cells were larger. These differences were largelv 
obliterated by administrating a synthetic anabolic steroid. The in- 
vestigators concluded that the age differences are not the result of 
irreversible alterations on the genome or in the translation transcrip- 
tion apparatus. 

At the VA Hospital. Cincinnati, Ohio, investigators found that the 
incidence of lymphocytotoxins in men and women increased with age. 
the increase being greater in the 60's and 70's than in the 20's through 
the 50's. The results reflect minor histocompatibility reactions con- 
sistent with the autoimmune theory of aging. 

Studies of age differences in the composition of blood serum indi- 
cate that serum copper concentration increases very slightly between 
the ages of 20 and 80 years in males but not in females. Serum 
ceruloplasmin on the other hand did not increase. 

Bone and connective tissue continues to receive attention. At the VA 
Hospital. Martinsburg, W. Va., two collagen cross-link ages have been 
identified in the rat uterus and their relationship to age determined. 

Investigators of the VA Hospital, Sepulveda, Calif., studied the 
properties of mitochondrial DXA in sea urchin eggs and in embryos 
containing 4 to 200 cells. The mitochondrial population of dividing 
and non-dividing mature cells is believed to be continuously removed ; 
disturbances in this replication could cause dysfunction or death in 
aging cells. 

Alcoholism and Drug Dependence 
Drugs 

Extensive research on drugs with abuse potential was performed at 
VA Hospitals in fiscal year 1975. The results will improve the psycho- 
logical assessment and therapy of drug dependent patients as well as 
increase knowledge of the mechanisms of action, metabolic effects and 
adverse reactions of these drugs. 

At the VA Hospital. Philadelphia, Pa., investigators reported on 
the sexual problems of heroin addicted and methadone maintained 
veterans, emphasizing the frequency of such problems. 

Investigators at the VA Hospital, Wood. Wis., designed and tested 
a rating scale which enables physicians to assess the degree of narcotic 
addiction in drug dependent patients. A clinical trial showed the 
rating scale to be accurate and to be useful in the treatment of narcotic 
withdrawal. 

In other studies at Wood. Wis., morphine was found to have an 
effect on cellular respiration. The pain-killing effect of morphine 
apparently i^ not due to this effect because other similar pain-killing 
drugs (methadone and pentazocine) do not have the same cellular 
act ion. 

Two studies, conducted at the VA Hospital, Palo Alto, Calif., have 
added to knowledge of dell a-D-tet rahydrocannabinol (tne active in- 
gredient of marijuana). In one, a new technique for detecting delta-9- 
THC in the urine was developed; in another, the effects of delta-D- 
TH( ' on blood sugar and on some of the hormones which control blood 



21 

sugar were investigated. Large doses of delta-9-THC given by vein 
impair the normal mechanisms for clearing excess sugar from the 
blood. At doses achieved by inhalation, however, this effect is minimal. 

In another study, also at Palo Alto, the use of propranolol (a widely 
used drug for cardiovascular disease) in the treatment of withdrawal 
from narcotics was assessed. Although previous studies suggested that 
propranolol was a narcotic antagonist, no such action Avas found. 
Propranolol did give some symptomatic relief during narcotic with- 
drawal but not enough to outweigh the potential harmful effects of the 
drug. 

The effect of barbiturates on the metabolism of norepinephrine, a 
normal chemical compound in brain and nerve tissue, was studied by 
investigators at the VA Hospital, Houston, Texas. They demonstrated 
that breakdown products of norepinephrine Ave re altered both in 
amount and in quality, providing insight into the action of bar- 
biturates on the brain. 

Alcohol 

Many investigators at VA Hospitals have focused on the metabolism 
and toxicity of alcohol and the complications of alcoholism. Only a few 
of the published studies can be mentioned. 

At the VA Hospital. Bronx. X.Y., alcoholic disease was the subject 
of a multi-faceted approach. In rats, a good animal model for the early 
stage of alcoholic liver disease, acetaldehvde (the first breakdown 
product of alcohol) reached a significantly higher blood level in 
alcoholics than in nonalcoholics given the same amount of alcohol. 
Since acetaldehvde is toxic for liver, heart and brain, this observation 
may explain some serious complications of alcoholism. Acetaldelryde is 
normally burned by the cell's mitochondria, a function damaged after 
chronic alcohol consumption. 

Studies of more advanced liver disease were accomplished in the 
baboon and have now been completed: they document the production 
of alcoholic hepatitis and even cirrhosis in baboons fed alcohol chroni- 
cally. This model has given the best approximation of human alcoholic 
disease and. hopefully, its use should improve understanding of the 
development and treatment of severe complications of alcoholism. 
Effects of alcohol on organs other than the liver were also studied in- 
cluding damage to the small intestine caused by large doses of orally 
administ ered alcohol. 

A study of the VA Hospital. Cincinnati. Ohio showed that the acute 
administration of alcohol, in moderate doses, enhances absorption of 
fat by the small intestine. 

At the VA Hospital. Togus, Maine, a clinical evaluation of lithium 
therapy in alcoholic veterans indicated that the metal had a marked 
beneficial effect on the drinking habits of alcoholics. The effect of 
lithium was not due to its anti-depressive properties, but. regardless of 
its mechanism, the regimen appears to be potentially useful. 

Investigators at the VA Hospital. Indianapolis. Ind.. found abnor- 
malities in vitamin B, metabolism which they attributed to the direct 
action of acetaldehvde. the major breakdown product of alcohol. 

An investigator at the VA Hospital, Albuquerque. X.Mex.. re- 
ported that white blood cells from alcoholic patients behaved as im- 



22 

mature cells due either to vitamin deficiency or to the direct toxic effect 
of alcohol. This may help explain the increased incidence of infection 
of alcoholic patients. 

The psychologic aspects of alcoholism were widely investigated at 
VA hospitals during the past year. In one such study, a new approach 
to alcoholic patients was taken at the VA Hospital, Coatesville, Pa. 
Alcoholics in the treatment program chose whether they would con- 
tinue to drink without fear of being expelled from the program or 
would stop. About half chose not to drink and half of those who chose 
to drink stopped during the treatment period. It became clear that 
patients who abstained had a better prognosis for treatment than those 
who did not. 

Audiology and speech pathology 

Investigators at the VA Hospital, Minneapolis, Minn., have differ- 
entiated four types of aphasic patients who were formerly pooled 
under one heading of "auditory comprehension problems." The investi- 
gators reported typical test scores for each of these patient categories 
and indicated therapeutic techniques specifically designed for each. 
Data from this study provide the means for more efficient, effective 
speech therapy for the long-term aphasic patient. 

In the same vein, a research report from the VA Hospital, Cleve- 
land, Ohio, assessed the capabilities of the most severely impaired 
aphasic patients to comprehend verbal instructions. These investi- 
gators have proposed new criteria for evaluating responses from global 
aphasic patients to tease out selective factors that are still operating in 
the communication link from comprehension to expression. 

Research at the VA Hospital, St. Louis, Mo., has focused on evaluat- 
ing the teaching of American Indian sign language to patients with 
various types of severe oral communication disorders. Patients using 
this type of sign language demonstrated marked improvement on 
verbal test items suggesting that the language stimulation by signing 
facilitated the verbal output of these patients. It was also found that 
untrained viewers could read Indian signs. 

Research at the VA Hospital, Syracuse, N.Y., added to the grow- 
ing body of literature on the effects of acupuncture on nerve deafness. 
The investigators, using double-blind techniques on two matched 
groups of hearing-impaired adults, found that those subjects receiving 
acupuncture treatments at the body site designated for hearing showed 
no difference in their test results using standard audio-metric evalua- 
tion techniques. 

In the control group, some subjects received up to 8 control treat- 
ments in sites not related to hearing or deafness, such as those for 
gastrointestinal changes. This group had no significant audiometric 
changes over the course of (he study. Subjective reports from a number 
of the study subjects did indicate improvement in their hearing, par- 
ticularly for background noises. 

Cardiovascular disorders 

The effect of environmental pollutants on patients with cardio- 
vascular disorders has been of substantive importance to investigators 
in the VA for the past several yew*. Thus a study at VAH, Long 



23 

Beach, Calif., showed that cigarette smoking and breathing carbon 
monoxide by patients with angina pectoris produced the reported 
cardiovascular hemodynamic changes during smoking of nicotine- 
containing cigarettes including elevated blood pressure and heart rate. 
Depression of the heart's ability to contract was related not to the 
nicotine content but rather to the presence of carbon monoxide in the 
inhaled smoke. These observations further delineated the deleterious 
effects of smoking on patients with angina pectoris. 

Physicians have long suspected that cigarette smoking reduces blood 
flow in the extremities but it has not been clear whether the cause was 
the smoking per se or the associated deep inspirations. A group of in- 
vestigators at the VA Hospital, Allen Park, Mich., demonstrated that 
blood flow is reduced by approximately 50 percent in the lower ex- 
tremities and that the cause is the inhalation of the smoke from ciga- 
rettes, not the associated deep breathing. 

Investigators at the VA Hospital, Bronx. X.Y., reported the re- 
sponses of industrial physicians who were asked whether they would 
hire patients with various cardiovascular, pulmonary and psychiatric 
illnesses. Despite great strides in treatment and rehabilitation, the 
physicians expressed a considerable, though variable, reluctance to hire 
patients with myocardial infarcation, angina pectoris, rheumatic heart 
disease, hypertension, renal disease, diabetes, tuberculosis and previous 
psychiatric illness. A concern for liability for further illness and a 
possible increase in the cost of compensation insurance were contribut- 
ing factors in more than 85 percent of the negative responses. 

The kidneys of individuals from industrialized areas contain more 
cadmium than do those of persons from underdeveloped nations. Cad- 
mium has been considered to be a potential source of cardiovascular 
disorders. Investigators at the VA Hospital, St, Louis, Mo., have de- 
veloped a new and sensitive technique for determining cadmium in the 
blood and urine called Graphite Furnace Atomic Absorption Spectro- 
photometry. This should prove valuable in further assessing the role 
of cadmium in human cardiovascular disorders. 

Also at St. Louis. VA investigators found that the height of the 
diastolic hypertension is positively related to the degree of cognitive 
dysfunction as measured by a psychological test used to diagnose brain 
damage. Thus high blood pre>sure not only increases the risk of strokes 
and transient ischemic attacks but can also adversely affect the mental 
acuity of patients whose blood pressure remains consistently in the 
hypertensive range. 

Investigators at the VA Hospital. Cleveland. Ohio, studied the ef- 
fects of an enzyme that converts angiotensin to its active form, demon- 
strating that the enzyme also hydrolyzes bradykinin and its higher 
homologues, Bradykinin is a substance associated with phvsiologic 
changes during inflammation. Enzymes that degrade it could therefore 
control the extent of inflammatory reaction. 

Atherosclerotic heart disease 

Mass screening for coronary risk factors was performed in more 
than 2.500 asymptomatic adults in southern California. The prevalence 
of elevated serum cholesterol, increased triglycerides, hypertension, 



24 

cigarette smoking, early signs of diabetes and obesity was confirmed in 
this subset of the population and high incidence of abnormal EKG's 
was found. This study emphasizes the importance of physician follow- 
up. Of equal importance is transmitting results to the patient and pro- 
viding him with enough information to act intelligently in reducing 
his risk of coronary atherosclerosis. 

The VA Cooperative Drug Lipid Study was the first to attempt to 
answer the question of which drugs effectively lowered serum choles- 
terol. A derivative of nicotine acid, aluminum nicotinate, was shown 
to reduce cholesterol levels whereas estrogen did not. Although the 
sustained cholesterol-lowering effect of dextrothyroxine was reaffirmed, 
the agent is no longer used because of its potential cardiotoxicity. 

In another report, the long-term effect of a drug, halofenate, was 
described. This drug does not significantly affect mean serum choles- 
terol levels, but is of value in treating hypertriglyceridemia and hyper- 
uricemia, the former being identified as a secondary risk factor in 
atherosclerotic heart disease and the latter being a common accom- 
paniment. 

Findings were reported on the effects of a new agent, tolamolol, on 
the cardiac function of patients with angina pectoris. Tolamolol is a 
beta-blocking agent which has more effect on the cardiac beta receptors 
than on those in other organs and hence causes fewer side effects, par- 
ticularly in patients with coexisting pulmonary disease. This agent 
produced a 25 percent increase in exercise time in some, but not all, 
patients with angina pectoris. 

YA investigators were also able to demonstrate an effect of sub- 
lingual nitroglycerin on myocardial function in patients with coro- 
nary artery disease. Many patients with coronary artery disease have 
areas of the heart that contract poorly. Sublingual nitroglycerin im- 
proved the ability of the heart muscle to contract, as measured b} T ven- 
triculography, presumably because it relieved myocardial ischemia. 

Basic science research 

Contributions to the understanding of cardiovascular disturbances 
were made through research in the biochemistry or physiology labora- 
tories when direct investigations on human subjects were inappropri- 
ate 1 . A series of investigations at the VA Hospital, Durham. N.C.. 
increased understanding of myocardial blood flow during exercise and 
ischemia. The investigators utilized new techniques that permitted 
measurements in the awake, active animal and compared these to 
studies in the same animal after anesthesia and chest surgery thus 
illustrating the dangers of extrapolating data from anesthetized, 
thoracotomized animals to awake, active animals. The amount of blood 
flowing to the endocardium, an area particularly vulnerable to myo- 
cardial ischemia and infarction, was measured in awake animals at rest 
and during exercise. 

Cardiac denervation did not impair the ability of coronary vascu- 
lature io respond to brief periods of ischemia, demonstrating the im- 
portance of local factors in the control of coronary vascular resistance 
by determining myocardial blood flow distribution during ischemia in 
the unanesthetized animal. The investigators demonstrated that with 
significant, coronary stenosis, ischemia-induced coronary vasodilation 
resulted in redistribution of the flow away from the subendocardial 
region leaving it vulnerable to myocardial damage or infarction. 



25 

Myocardial function in shock was explored by investigators at the 
VA Hospital, Oklahoma City, Okla. The presence of a circulating 
myocardial depressant in shock has been postulated but the investiga- 
tors were unable to demonstrate impairment of function by depressant 
factors circulating through the heart from an ischemic splanchnic 
region. With endotoxin shock, marked myocardial depression was 
demonstrated. 

A number of studies dealt with biochemical or electrophysiological 
aspects of the heart and blood vessels. A report from the VA Hospital, 
Philadelphia, Pa., emphasized the importance of vessel wall disturb- 
ances of lipid metabolism in the production of atherogenesis. Metabo- 
lism of fatty acids by aortic mitochondria was altered by cholesterol 
feeding and this may lead to increased esterification of cholesterol. 
Esterined cholesterol has a reduced exchange potential and thus may 
remain •'trapped'' in the aortic wall. 

The effect of ischemia on the conducting tissue of the heart was 
evaluated in animals by investigators at the VA Hospital. Miami, Fla. 
They observed that, although the conducting tissue in the subendo- 
cardial regions are early affected by infarction, many Purkinje cells 
apparently resist, survive the infarction and return to normal function. 

Investigators at the VA Hospital, Madison, Wise, studied the ef- 
fects of myocardial ischemia on intermediary metabolism in the heart. 
Ischemia decreases fatty acid oxidation and this may lead to an 
accumulation of substances that inhibit the metabolism of adenine 
nucleotides. The net result would be a lower energy charge of the cell 
with diminished muscle contraction and electrical condition in the 
ischemic myocardium. 

Investigators at the VA Hospital. Minneapolis, Minn., developed 
evidence that the myocardial cell concentration of calcium is related 
to stimulation of RXA and protein synthesis thus extending knowl- 
edge of the effect of catacholamines which increase intracellular cal- 
cium concentration on RXA and protein synthesis. This may help 
explain the influence of autonomic nervous system activity on RXA 
and protein synthesis. 

An investigator at the VA Hospital, Houston, Texas, developed a 
new technique for measuring beat-to-beat movement of calcium ions 
across the cell membrane, a tool that enables one to define more pre- 
cisely the site of action of drugs that significantly affect myocardial 
contractility. 

Several studies dealt with the control of the peripheral circulation. 
Investigators in the VA Hospital, Iowa City, la., demonstrated the 
regional vascular effects of vasopressin, a hormone produced by the 
posterior pituitary. The hormone had significant effects on blood ves- 
sels in the muscle, mesenteiy and kidney. 

Cardiovascular surgery 

The coronary artery bypass is one of the most frequent cardiovas- 
cular operations. The question remains as to which type of graft is 
better, the internal mammary arterial or the aorto-coronary venous 
graft. Investigators at the VA Hospital. Palo Alto. Calif., reported 
experience with both types of grafts in animals fed normal and hyper- 
lipidemic diets. The internal mamary arterial grafts and better long- 
term patency: in the normal lipemic condition, the arterial grafts 
underwent less histologic change; and both types of grafts were more 



26 

susceptible to atheromatous change than the host's vessels. They are 
also investigating the problem of ischemic myocardial injury in human 
operations when the aortic valve is replaced and a coronary artery 
bypass graft is inserted. In many hospitals, the mortality rate for the 
combined operation is much higher than for either operation alone. 
Similarly, evidence of ischemic myocardial injury is higher in the 
combined operation. 

Serum enzyme changes are important indicators of myocardial 
damage and minimal elevation of the serum enzymes can occur follow- 
ing cardiac catheterization and coronary angiography when myo- 
cardial damage may result. Investigators associated with the VA 
Hospital. Houston, Texas, evaluated serum enzyme changes following 
cardiac catheterization and coronary angiography. The values did not 
increase signficantly following these procedures except when intra- 
muscular medications were given. 

A therapeutic dilemma faces the cardiologist whose patient has 
chronic bi fascicular block. Investigators at the VA Hospital, Chicago 
(WS), 111., investigated the significance, mechanisms and clinical im- 
plications of chronic bifascicular block and demonstrated the specific 
indications for which peacemaking is required. The problem has now 
been put in clinical perspective and the initial enthusiasm for using 
pacemakers in all of these patients has been tempered through this 
careful analysis. 

Investigators at the VA Center, Hampton, Va., described the hemo- 
dynamic effects of ethaverine hydrochloride on patients with periph- 
eral vascular disease. A significant increase in muscle blood flow 
occurred in patients with atheromatous obstruction, suggesting that 
this agent might benefit these patients. 

Clinical experience with pericardial infusion in uremic patients was 
reported from the Y A Hospital, Nashville. Tenn. This common and 
frequently resistant form of pericarditis was effectively treated under 
certain circumstances by pericardiectomy. 

Atherosclerotic heart disease and its complications 

Complications of acute myocardial infarction include shock, con- 
gestive heart failure and cardiac arrhythmias of which the latter is by 
far the most common and potentially lethal. Prediction of one lethal 
arrhythmia, ventricular tachycardia, has been based on certain char- 
acteristics of ventricular premature beats. A group of investigators at 
the VA Hospital, Little Rock, Ark., have shown that the degree of 
prematurity of the ventricular premature beat in fact does not corre- 
late well with the subsequent development of ventricular tachycardia. 
This observation may help prevent recurrent ventricular tachycardia 
and lead to better understanding oi its pathogenesis. 

Investigators also characterized the arrhythmias that occur during 
the course of acute myocardial infarction. One arrhythmia previously 
thought to be uncommon accelerated ventricular rhythm, was present 
in nearly 50 percent of patients. Furthermore, it did not always indi- 
cate a benign prognosis. 

At the YA Hospital, Dallas. Texas, investigators further charac- 
terized some of the hormonal changes that occur during acute myo- 
cardial infarction. Serum glucagon levels rose significantly, particu- 
larly in patients wit h infarct ion and shock'. The Increase in blood sugar 



27 

found in patients with shock complicating myocardial infarction was 
related to this rise in serum glucagon and to a relative insulin 
deficiency. 

Atherosclerotic heart disease involves predominantly the left ventri- 
cle and many assume that right ventricular dysfunction, as a direct 
result of atherosclerotic heart disease, is distinctly unusual. Three find- 
ings by VA investigators in Miami and Washington. D.C., suggest 
that, under certain circumstances, right ventricular function is directly 
impaired in atherosclerotic heart disease. The Miami investigators doc- 
umented the incidence of dysfunction of the right ventricle in coro- 
nary artery disease. The Washington. D.C., VA investigators noted the 
association of right ventricular infarction with diaphragmatic infarc- 
tion of the left ventricle. These clinical observations were supported by 
laboratory investigations in which significant right ventricular dys- 
function was produced in an experimental animal. 

Also, investigations at the Washington, D.C., VA Hospital into 
afterload reduction in the treatment of heart failure helped pioneer 
research into another aspect of cardiovascular disease. Results of one 
study indicate the importance of arterial pressure as a determinant 
of left ventricular filling pressure after acute myocardial infarction. 
Another study extends the concept of afterload reduction to the treat- 
ment of refractory heart failure in 18 patients with chronic intractable 
decompensation secondary to ischemic heart disease and cardiomyop- 
athy; nitroprusside infusions significantly improved both hemody- 
namics and symptoms. 

Graphic techniques 

VA investigators continue to play leading roles in electrocardiogra- 
phy and vectorcardiography. Two investigators from the VA Hospital, 
Washington, D.C, described the diagnostic usefulness of frontal plane 
QRS loop rotations in the Frank vectorcardiogram in over 1,000 cases 
and the usefulness of computer analysis of the orthogonal electrocarcli- 
orgram and vectorcardiogram in mitral stenosis. 

Other VA investigators have studied echocardiography in the diag- 
nosis of cardiovascular disorders. They described the echocardio- 
graphy manifestations of flail aortic leaflets in bacterial endocarditis, 
and reaffirmed the usefulness of echocardiography in the diagnosis of 
pericardial disorders. 

Investigators at the VA Hospital, Salt Lake City, Utah, described 
the simple, safe, noninvasive technique of plethysmography monitor- 
ing in patients undergoing vascular reconstruction, sympathectomy 
and injection of chemical vasodilators. 

Others, at the VA Hospital, San Diego, Calif., described the utility 
of ballistocardiography as a technique to compare cardiovascular 
events in a variety of species, including mouse, man and the whale. 

VA investigators described the usefulness and the limitations of the 
3rd and 4th heart sounds in the evaluation of patients with cardio- 
vascular disorders. 

Measurement of the severity of stenosis in heavily calcified aortic 
valves was accomplished by investigators at the VA Hospital, Okla- 
homa City. Okla., using measurements obtained from plain film 
orifice-view roentgenograms, a simple and safe noninvasive procedure. 

Investigators at the VA Hospital, Denver, Colo., described a tech- 



28 

nique for measuring the left heart ejection fraction and end-diastolic 
volume by a computerized, scintigraphic technique utilizing a wedged 
pulmonary arterial catheter and technetium-99m. 

Endocrinology and metabolism 

Diabetes mellitus 

Major progress in the understanding of diabetes mellitus continues 
to be made through studies at several VA hospitals especially on the 
role of glucagon. The advances began with the development of radio- 
immunoassays for insulin at the VA Hospital, Bronx, N.Y. The assays 
revealed that insulin secretion may be slow in adult onset diabetes 
but the absolute levels of insulin can be elevated rather than depressed. 
Development of the first successful glucagon assay at the VA Hospital. 
Dallas, Texas led to the discovery that an elevation of glucagon is a 
characteristic of diabetes mellitus. More recently the Dallas studies 
were extended to show that hyperglucagonemia is a characteristic of 
all types of glucose elevation. 

Elucidation of the role of glucagon in the development of diabetic 
hyperglycemia was made possible by the discovery of another hor- 
mone, somatostatin, simultaneously at the VA Hospital, New Orleans. 
La., and at the Salk Institute. This hormone was soon shown to de- 
crease the secretion of both glucagon and insulin. With the aid of 
somatostatin VA investigators at Dallas have now found thta glucagon 
plays an essential role in the development of diabetic hyperglycemia. 
In fact, if glucagon is suppressed it is not possible to produce an ele- 
vation in blood glucose despite the complete absence of insulin. It is 
becoming increasingly likely that glucagon is a ke} T hormone in the 
development of diabetes. Moreover, with means available for sup- 
pressing glucagon, these new discoveries open the way to new ap- 
proaches to the treatment of diabetes. 

It had been assumed that glucagon is secreted only by pancreatic 
cells but the Dallas investigators have now shown that, in the absence 
of the pancreas, glucagon secretion is increased rather than depressed. 
Large amounts of glucagon can be produced by cells located in the 
stomach and the upper intestine. The importance of this gastrointes- 
tinal glucagon in the production of the diabetic syndrome is the sub- 
ject of active study. 

Investigators at the VA Hospital, Memphis, Tenn., have reported 
the most complete studies yet available on the treatment of diabetic 
ketoacidosis using low doses of insulin rather than the conventional 
high-dose therapy. This treatment of diabetic ketoacidosis is simpler, 
sa fer, and just as effective as high-dose therapy. 

The finding that diabetics may secrete insulin at slower than normal 
rates hut reach higher than normal absolute levels of insulin in adult 
onset diabetes has been explained by VA investigators at Palo Alto. 
Calif. The hyperglycemia of diabetes may be due in part to resistance 
of various diabetic tissues to the effects of insulin. They reported evi- 
dence of such insulin resistance emphasizing a little-recognized aspect 
of the diabetic syndrome. The Palo Alto investigators farther indi- 
cated that the resistance of diabetic tissues t<> insulin may he due to 
a decrease in the numbers of binding sites for insulin on the surface 
of the individual cells of the diabetic. 



29 

Studies of diabetic vascular disease are continuing at a number of 
VA institutions, particular!}' at Dallas. Texas and San Francisco. 
Calif. Most patients with inherited diabetes have a thickening- of the 
portion of their capillaries known as the basement membrane, a lesion 
apparently specific for genetic diabetes in the adult. Recent collabora- 
tive studies between the Dallas and San Francisco VA Hospitals have 
shown that this characteristic capillary lesion of diabetes is not seen 
regularly in diabetic children. The vascular abnormality is almost 
always present by the time the diabetic reaches adulthood, suggesting 
that effective prophylaxis of diabetic vascular disease should be con- 
centrated in the childhood years. 

Calcium and bone disease 

Rapid progress has been made in the field of bone metabolism, par- 
ticularly in the area of parathyroid hormone abnormalities. Routine 
screening for elevated serum calcium has disclosed abnormalities in 
the hormones, particularly parathormone and calcitonin, that control 
calcium levels and bone metabolism. Hormones produced by parathy- 
roid tumors often cause bone disease but lung cancers can make a 
hormone that acts like parathyroid hormone. The commonest cause 
of elevated calcium levels in the age group seen in VA hospitals is 
cancer, particularly of the lung. 

VA investigators at San Diego. Calif., have pioneered the develop- 
ment of sensitive methods for measuring parathyroid hormone and 
have more recently shown that they can differentiate true parathy- 
roid hormone from the substance produced by cancer cells. Such meas- 
urements of specific hormones can be used as a means of early 
diagnosis of both parathyroid tumors and lung cancer. 

Recent studies at the VA Hospital, Chicago (WS), 111., have indi- 
cated that many common drugs, such as aminophyline used to treat 
asthma, may markedly influence parathyroid hormone secretion. The 
investigators have also demonstrated that in usual doses, steroid hor- 
mones may have a similar effect on parathyroid hormones. 

Recent interest in calcitonin, another hormone influencing calcium 
metabolism, has increased greatly. Again the Endocrinology Unit at 
the VA Hospital, San Diego. Calif., has perfected methods for meas- 
uring calcitonin and has developed a simple, sensitive test for discov- 
ering calcitonin secreting tumors. Studies both in San Diego and 
at the VA Hospital. Indianapolis. Ind., have used either isolated 
thyroid glands or calcitonin-producing cells in tissue culture to ex- 
amine the fundamental mechanisms by which calcitonin secretion is 
controlled. These studies have made it possible to study the control 
of calcitonin synthe.-is and have demonstrated that calcitonin is first 
synthesized as a pro-hormone which is later converted into the active 
compound. 

These fundamental studies, coupled with their prompt clinical ap- 
plication are rapidly improving diagnostic and therapeutic approaches 
to the boTie diseases in veterans. 

Atherosclerosis and lipid disorders 

The basic causes underlying the accumulation of cholesterol and 
triglycerides in the blood and arteries are being studied by investi- 
gators at the Palo Alto VA Hospital. Their evidence supports the 
concept that a high triglyceride level in man is frequently caused by 



30 

elevated levels of insulin and that diets high in carbohydrate may 
produce hypertriglyceridemia through such an insulin-stimulating 
mechanism. The increase in triglycerides seen in mild, adult onset 
diabetics may likewise be due to an absolute excess of insulin. This 
increase in triglycerides may predispose the diabetic to develop pre- 
mature atherosclerosis. 

Fundamental studies of cholesterol disorders in man at the VA 
Hospital Center, Los Angeles (Wadsworth), Calif., indicate that 
white blood cells from patients with an inherited form of hypercholes- 
terolemia have a defective control mechanism for regulating choles- 
terol synthesis. One cause of atherosclerosis in man may be detectable 
-imply by studying cholesterol synthesis in readily obtainable blood 
samples. The Wadsworth investigators have also discovered a new 
pathway by which the major building blocks of cholesterol can be 
converted to carbon dioxide. This may constitute a means by which 
the body controls the synthesis of cholesterol. 

Alcoholism 

One of the most serious complications of acute alcoholism is a sud- 
den lowering? of the blood glucose leading to convulsions and death. 
The mechanism is unknown but alcoholic hypoglycemia could be due 
to a reduced ability of the liver to synthesize glucose. Studies from the 
San Francisco VA Hospital have, however, demonstrated that the 
initial effect of alcohol is to increase glucose utilization rather than 
decrease glucose production. This effect is more marked in thin than 
in obese individuals. 

Arthritis 

Studies at the Wadsworth VA Hospital have shown that certain 
cell surface antigens are related to specific types of arthritis in man. 
Patients with crippling arthritis of the spine, called ankylosing spon 
dylit is. have an extremely high incidence of cell surface antigen termed 
HLA/W-27. Patients with the arthritis that accompanies psoriasis 
and arthritis which accompanies urethritis and inflammation of the 
bowel likewise have a High incidence of ITLA AY-27. This has made it- 
possible to use the ITLA test to diagnose previously unrecognized 
forms of arthritis and therebv to treat the disease before it cripples 
the patient. 

Discovery of the relationship between psoriasis, inflammatory bowel 
disease, urethritis and ankylosing spondylitis suggests a common un- 
derlying cause of these conditions which previously had been assumed 
to be unrelated. Discovery of the relationship between 1ILA/W-27 

and these types of arthritis represents one of the most important dis- 
coveries m the rheumatology field during the past five years. 

Gastroenterology 

Diseases of the gastrointestinal tract are associated with a high mor- 
tality ( lo percent ) and a significant morbidity. An estimated SA mil- 
lion persons per year are hospitalized for a variety of digestive diseases 
and about L3 million Americans are affected by chronic digestive con- 
ditions. Gastroenterology research in the VA hospital system has been 
growing both m scope and in quality. It has emphasized investigation 
ol the pathophysiologic basis for gastrointestinal disorders, of new 



31 

techniques for diagnosis and management and of prevention and 

treatment. 

Esophagus and stomach 

The lower esophageal sphincter largely determines how much gas- 
tric acid remixes into the esophagus. A continuous reflux of gastric 
acid due to an incompetent sphincter is associated with inflammation 
of the esophagus which eventually mav lead to a stricture. Important 
advances were made at the VA hospital (Wadsworth), Los Angeles, 
Calif. Gastric alkalinization did not cause an elevation of gastrin nor 
an increased sphincter pressure. These investigators confirmed the de- 
crease of lower esophageal sphincter pressure by intestinal hormones 
such* as cholecvstokinin in pharmacological doses raising the question 
of whether gastrin and cholecvstokinin regulate lower esophageal 
sphincter pressure under physiological circumstances. Investigators 
from the West Haven, Conn. VA Hospital have provided good evi- 
dence that a surgical approach (anterior fundoplication) for the 
treatment of reflux is effective since it restores the sphincter function 
to normal. Two drugs. Bethanecal and Metoelopramide, produced a 
significant increase in sphincter pressure with improvement in the 
symptoms of reflux without significant side effects. These new thera- 
peutic approaches will influence the management of this common clin- 
ical problem. 

Productive studies of the factors responsible for gastric acid sec- 
retion and gastric propulsion are being conducted at the TVadsworth 
VA Hospital. These factors may be related to the pathogenesis of 
duodenal and gastric ulcers. Gastrin, a known stimulator of gastric 
acid secretion, is secreted by the specific cells in the antrum of the 
stomach and duodenum but its role in the pathogenesis of duodenal 
ulcer has not been established. 

Investigators at Wadsworth have demonstrated that patients with 
duodenal"ulcer not only secrete more acid in response to stimulation 
by pentagastrin but also are more sensitive to gastrin; that is. they 
need smaller dcses of pentagastrin to achieve the same fraction of the 
maximal response. 

Also, at the same hospital, investigators have shown that gastrins 
with a different number of amino acid residues differ in their ability 
to stimulate gastric acid secretion. Separation of various gastrins 
could shed more light on the role of these hormones in the regulation 
of gastric acid secretion in normal subjects and in patients with duo- 
denal ulcer. 

Therapeutic trials of new drugs for treatment of the duodenal 
ulcer are now being conducted at Wadsworth and several other VA 
hospitals. H2 receptor blockers (Cimetidirie, Metiamide) are useful in 
suppressing gastric acid secretion in gastrin producing tumors (Zol- 
linger-Ellison Syndrome). Barring serious side effects, these may 
become therapeutic agents. In addition, investigators at Wadsworth 
are studying the possible therapeutic role of prostaglandin and secre- 
tin in the treatment of duodenal ulcer. 

Investigators at the VA Hospital, Salt Lake City, Utah, reported 
that prostaglandin, a known inhibitor of gastric acid secretion, is 
not decreased in patients with duodenal ulcer. Consequently, its 
deficiency probably is not a cause of duodenal ulcer. 



32 

Progress was also made in understanding factors regulating gastric 
emptying. VA investigators at Iowa City, la., have demonstrated the 
important role of the first part of the duodenum in the control of 
gastric acid secretion and gastric emptying. Choleeystokinin, a small 
intestinal hormone, also inhibits gastric emptying as its physiologic 
function. 

Studies to elucidate the pathogenesis of gastric ulcer include testing 
the hypothesis that bile salts can break the gastric mucosal barrier at 
the VA Hospital, West Roxbury, Mass. The high acidity of gastric 
juice augments the damaging effects of bile salts but the bile salt 
binding agent, cholestyramine, failed to prevent the toxic effects of 
bile salts on the gastric mucosa. 

Upper intestinal hemorrhage is frequently life-threatening. Investi- 
gators at the YA Hospital, New Haven, Conn., have shown that the 
intra-arterial administration of vasopressin does not improve survival 
and does not significantly decrease the necessity for surgical inter- 
vention. 

Pancreas and the biliary tract 

Diseases of the pancreas and biliary tract are one of the most com- 
mon disorders encountered in VA hospitals. Investigators at the VA 
Hosptial, Augusta, Ga., continued to provide information concerning 
transport, synthesis and secretion of pancreatic digestive protein in 
response to various gastrointestinal hormones. Several clinical, con- 
trolled trials at TVads worth, Los Angeles, and Richmond, Va., VA 
Hospitals on the medical treatment of acute pancreatitis will greatly 
assist physicians in treating this common disease. 

Investigators at the Richmond VA Hospital continued to study the 
hepatocellular regulation of bile salts, phospholipid and cholesterol 
metabolism in man and in experimental animals. The sensitivity and 
specificity of factors that control bile acid and cholesterol synthesis 
are being defined in man. These investigators have provided informa- 
tion about the role of bile salts in the transport of phospholipid and 
cholesterol from the site of synthesis into the liver and bile. Under- 
standing of the mechanism regulating hepatic lipid synthesis and 
transport may lead to a better understanding of diseases of lipid 
metabolism including cholesterol gallstones, hyperlipidemia and arte- 
riosclerosis. Investigators from Denver, Colo, and Richmond. Va., VA 
Hospitals have further defined the metabolic abnormality of secondary 
bile acid metabolism in patients with cirrhosis. 

Selective biliary obstruction may prove to be an important model 
for the study of lipid metabolism in cholestasis. Investigators at the 
AW Hospital, Syracuse, N.Y., demonstrated that the administration 
of B-glycerophosphate to human subjects greatly increases the solu- 
bility of cholesterol in bile and this agent may prove to dissolve chole- 
sterol gallstones. A thorough study in an unselected group of 100 pa- 
ents with gallstones at the VA Hospital, Philadelphia, Pa., showed a 
higher incidence of pigmented stones than previously reported. 

Progress is being made in diagnosing pancreato-biliary diseases by 
the use of endoscopic cholangiography and pancreatography. Gastro- 
enterologists at the YA Hospital, Minneapolis, Minnesota, have con- 
tributed to the development and improvement of these techniques. 



33 

Liver 

Many VA investigators are interested in live? disease. Research at 
the Bronx. X.Y. VA Hospital has contributed to the understanding 
of basic mechanisms of alcohol degradation and the toxic effects of 
alcohol on the metabolism of protein, carbohydrates, and fat, and has 
related these changes to clinical problems. The Bronx investigators 
have developed an experimental model of chronic alcoholism in ba- 
boons and used it to study the natural history of alcoholic injury. 
In these studies the animals developed fatty liver, alcoholic hepatitis 
and cirrhosis in spite of maintenance of an adequate diet. These in- 
vestigators also observed that the serum acetaldehyde. a degradation 
product of alcohol is higher in alcoholic subjects than non-alcoholics. 
Numerous toxic effects have been attributed to this compound, includ- 
ing mitochondrial damage, inhibition of oxidative phosphorylation, 
and decreased synthesis of myocardial protein. 

VA hospitals have tested several measures to improve the prognosis 
of chronic liver disease and its complications. The controlled study 
of portocaval shunt for gastrointestinal bleeding secondary to cir- 
rhosis showed no significant differences in survival between different 
types of shunts. 

More discouraging was the fact that no operation was significantly 
better than medical management. At the VA Hospital, West Haven, 
Conn., a controlled trial of chronic hepatic encephalopathy, a common 
complication of acute and chronic liver disease, demonstrated that a 
synthetic disacharide (Lactulose) is as effective in the treatment of 
these disorders as non-absorbable antibiotics. Prolonged use of non- 
absorbable antibiotics may cause kidney toxicity. Similarly, lactose 
can be useful in the treatment of hepatic encephalopathy in patients 
with a lactase deficiency. 

VA investigators at West Haven and Wadsworth have demonstrated 
the frequent existence of bacterial peritonitis during cirrhosis. Early 
recognition of this complication results in a better prognosis. Investi- 
gators at the VA Hospital. Syracuse. X.Y.. reported that cirrhotic 
patients have impaired absorption of micellar long-chain fatty acids, 
possibly related to portal or lymphatic hypertension contributing to 
maldigestion and malabsorption. It was reported from the Bronx. X.Y. 
VA Hospital that acute ethanol administration enhances intestinal 
lymph formation and fat transport. In contrast, chronic intake of alco- 
hol inhibits these effects, establishing the direct toxicity of ethanol on 
the gut. 

Investigators at the VA Hospital. Nashville, Tenn.. are studying the 
effect of liver disease on the disposition and elimination of a variety of 
drugs. The elimination of Meperidine. Paraldehyde. Phenobarbital 
and Diazepam in cirrhosis is slow because the drug metabolizing ac- 
tivity of the liver is impaired. These drugs should be used cautiously 
in patients with liver disease since they may precipitate hepatic coma. 
Another tranquilizer. Oxazepam, is eliminated normally in patients 
wtih liver disease and should provide a greater margin of safety. 

Investigators at the VA Hospital. Xew York. X.Y.. have observed 
that alcohol depresses albumin synthesis by the liver and causes marked 
disaggregation of the endoplasmic membrane bound polysome, an 



34 

effect which can be reversed by certain amino acids. These studies indi- 
cate another toxic effect of acute and chronic alcohol intake. 

Small intestine and large colon 

-Investigation of the small intestine was oriented mainly towards the 
physiological processes involved in the digestion of food and vitamins, 
including lactose intolerance which is a common clinical problem. 
Intolerance to milk is particularly high among blacks (in excess of TO 
percent). 

Investigators at the VA Hospital, Madison, Wis., have demon- 
strated that in children with T-cell deficiency, the presence of diarrhia 
and malabsorption is associated with histological features similar to 
that of Whipple's disease suggesting the possibility of defective host 
defense. The importance of oral lactose and sucrose tolerance tests as 
well as small intestinal histology in diagnosing chronic diarrhia in 
children has been demonstrated from the studies at the VA Hospital. 
Oklahoma City, Okla. VA investigators at San Francisco have eluci- 
dated various phases of protein absorption. At the VA Hospital, 
New York, X.Y.. it was shown that sodium taurochenodeoxycholate, 
as opposed to taurocholate, does not enhance cholesterol absorption. 
( nenodeoxycholic acid may be used in the near future as a medical 
therapy for dissolution of cholesterol gallstones in man. Inhibition 
of water absorption and reduced circular smooth muscle activity are 
probably the factors responsible for castor-oil and magnesium sulfate- 
induced catharsis, according to studies at the Madison VA Hospital. 
The mechanism of thiamine (B, vitamin) absorption has been eluci- 
dated by the investigators at the VA Hospital, Xashville, Tenn. 

In recent years small intestinal hormones have proved important in 
regulating gastric acid and pancreatic excretion, motor activity of the 
gut and absorption. VA Hospital investigators at Dallas, Texas and 
Wadsworth. Los Angeles, have contributed significantly to studies on 
the physiologic roles of secretin, gastrin, cholecystokinin, glucagon, 
and other ''candidate hormones" which are being continuously eval- 
uated in several VA hospitals. 

Hematology and sickle cell disease 

Anemias, hemoglobin and sickle cell anemia 

Several new mutations of hemoglobin have been identified by VA 
investigators. Hemoglobin Grady, a fast-migrating hemoglobin muta- 
tion of the a chain, was identified by researchers at the VA Hospital, 
Augusta. Ga. This mutation involves the insertion of three additional 
amino acids into the chain. These three amino acids are repeated in 
the adjacent sequence, suggesting that their duplication resulted from 
mismatched intragenic crossing-over. This is the first report of this 
type of mutation in hemoglobin. 

A new unstable hemoglobin variant, hemoglobin Ann Arbor, was 
di covered at the VA Hospital, Chicago (WS), 111. Its presence re- 
sulted in a hemolytic anemia. The mutant a chain is so unstable that 
ii is rapidly destroyed and leads to the unbalanced production of nor- 
mal a and /} chains. A patient with two mutant hemoglobins, Hope and 
Sickle, was studied at the V A Hospital. Jackson, Miss. Hemoglobin 



35 

Hope is unstable and. in combination with hemoglobin S, produces 
only a mild hemolytic anemia, much less severe than any of the 
recognized common sickling disorders. 

In a continuation of previous work, VA investigators at Augusta, 
Ga., have published comparative studies on the variants that have been 
described in the minor adult hemoglobin A 2 . The same laboratory has 
added to our understanding of the heterogeneity of human fetal 
hemoglobin in thalassemia and other related disorders. 

Investigators at the VA Hospital. Dayton. Ohio, described the oc- 
currence of multiple pulmonary emboli in a patient with hepatic cirr- 
hosis, portal hypertension and sickle cell trait. At autopsy the emboli 
were composed of sickled cells. Alcoholism may have contributed to 
the sickling but sickle trait is so prevalent that its occurrence with 
other rare clinical events may result merely from chance. Sickle cell 
trait is usually considered a benign condition. 

Zinc deficiency associated with delayed maturation was described in 
patients with sickle cell anemia by investigators at the VA Hospital. 
Allen Park, Mich. Five male adolescents responded to oral zinc ther- 
apy with evidence of sexual maturation: two increased significantly in 
height. The investigators are now determining whether zinc supple- 
mentation decreases the incidence of painful crises in persons with 
sickle cell anemia. 

The double-blind clinical trial of oral sodium cyanate has been com- 
pleted at the VA Hospital, Miami. Fla. Most patients had impres- 
sively prolonged red blood cell survival and increased hemoglobin 
levels while taking cyanate. The incidence of painful crises did not. 
however, decrease and significant toxicity was observed. Of 19 patients 
who completed the study, 7 had weight lo>s exceeding 5 percent, 4 
showed evidence of subclinical neuropathy which is reversible when 
the drug is stopped, and one patient developed cataracts. Orally ad- 
ministered cyanate was deemed unsafe and ineffective as treatment of 
sickle cell anemia. 

A new antisickling agent is. being studied at the VA Hospital. San 
Francisco. Calif. This chemical, dimethyl adipimidate. completely 
inhibits sickling and makes several properties of the treated sickle 
cell more nearly normal. It is one of a class of chemicals which interact 
with proteins and cross-link two or more molecules. Studies of this 
potentially useful compound are continuing in several collaborating 
laboratories. 

Investigators from the VA Hospital. Xorthport. X.Y.. described a 
remission with imnijanosuppressive drugs in a patient who had a pro- 
duction defect of red blood cells caused by a circulating antibody to 
red cell precursors. This is the fourth case of autoimmune pure red 
cell aplasia successfully treated in this manner. The three previously 
described cases were studied by VA investigators at Xashville, Tenn. 
The latter published the most extensive recent review of current 
knowledge regarding erythropoietin, the hormone which regulates red 
blood cell production. 

At the VA Center. Los Angeles (TTadsworth). Calif., researchers 
investigated a patient with hereditary hemolytic anemia caused by a 
previously unrecognizable variant of the red cell enzyme glycosephos- 
phate isomerase. The same laboraton^ reported a form of hereditary 



•0-799- 



36 

anemia resulting from an abnormality of the enzyme pyrimidine 5'- 
nucleoticlase in the patient's erythrocytes, and has defined the underly- 
ing problem of more types of hereditary hemolytic anemias due to 
enzyme abnormalities than any other laboratory in the world. 

An animal model was developed for the hemolytic anemia and 
bleeding disorder associated with clinical hyperalimentation at the 
YA Hospital, Minneapolis, Minn. Infusion of amino acids and glucose 
rapidly produced the clinical syndrome. A severe depression in serum 
phosphate led to secondary effects on the metabolism in red cells and 
platelets which resulted in a fall at ATP. The red cell survival and 
platelet function could be returned to normal by adding inorganic 
phosphate to the infusion mixture. In patients receiving hyperalimen- 
tation, impaired central nervous function and defective leukocyte func- 
tion have also been described and may be due to the same metabolic 
derangement from phosphate depletion. 

At the VA Hospital, Chicago (AYS), 111., studies of both animals 
and man have revealed large numbers of peripheral blood cells which 
are able to form new colonies of cells in culture. Nearly 80 percent of 
the cells retain this capacity after cryopreservation for 30 days. Stored 
peripheral white blood colls promptly repopulated the marrow after 
supralethal irradiation in animals. Thus peripheral blood may be 
potentially useful for marrow grafting purposes. 

Hydroxyethyl starch has been studied as a cryoprotective agent in 
frozen-thawed blood in monkeys at the VA Hospital, Ann Arbor, 
Mich. This protective agent need not be separated from the blood prior 
to its transfusion; other agents such as DMSO and glycerol, must be 
removed. The frozen blood protected monkeys against shock and 
caused no bleeding problems. Previous reports indicated that hydroxy- 
ethyl starch caused platelet clumping and coagulation abnormalities 
but no pathological changes due to the hydroxyethyl starch could be 
identified at autopsy. This type of cryoprotective agent would save 
time and money if it can be proved safe. 

Vitamin B r > and pernicious anemia 

At VA Hospital, Albany, X.Y.. improved methods have been de- 
veloped for measuring several different plasma vitamin Bi 2 binding 
proteins. The techniques may differentiate closely related blood dis- 
orders, such as polycythemia vera and chronic myelocytic leukemia, 
in which different types of vitamin B 12 binding proteins are elevated. 
Studies of blood eosinophils (cells which are increased in allergic, 
parasitic, and skin diseases) in mice at the YA Hospital, Nashville. 
Tenn., have revealed that there is great diurnal variation in their 
circulating numbers. At midday the eosinophil count is maximal and 
it is minimal around midnight. Removing blood from animals mark- 
edly increased the circulating eosinophils for nearly 24 hours. Little 
is known about the regulation of eosinophils proliferation but this 
work is now being extended to man. 

Investigators at the YA Los Angeles (Wadsworth) Calif. Center 
using highly sensitive immunologic techniques demonstrated that 
nearly all patients with pernicious anemia have evidence of cellular 
immunity against hog stomach intrinsic factor. Previous studies have 
shown that circulating antibodies to intrinsic factor and to stomach 
cells are present in at least some patients with pernicious anemia. 



37 

Whether this altered immunity causes the disease or results from it is 
unknown but patients with other abnormalities of the gastrointestinal 
tract do not possess the antibodies. 
Bleeding disorders, platelets and blood coagulation 

Investigators at the VA Hospital, Durham, X.C., developed a 
method to detect and measure antibodies on the surface of blood 
platelets. This assay confirmed the diagnosis of idiopathic autoim- 
mune thrombocytopenic purpura. Patients with greater quantities of 
antibody on their platelets were refractory to adrenal steroid therapy. 

At the YA Hospital, Bronx, N.Y., a patient was studied with 
immune thrombocytopenic purpura resulting from aspirin ingestion. 
Though ingestion* of aspirin is frequently associated with clinical 
bleeding this is only the third time that such bleeding has been 
ascribed to an immune basis. VA investigators in Madison. Wis., 
reported on a patient with immune thrombocytopenia associated with 
ingestion of chloropheniramine. an antihistamine. This is the first 
report of thrombocytopenia due to this drug and only the second case 
described as drug-induced immune thrombocytopenia associated with 
any frequently used antihistamine. 

At the YA Hospital, Miami, Fla., a patient who bled extensively 
after an operation had been taking clofibrate. Xylocaine was used as 
the local anesthetic. These two drugs were profoundly synergistic in 
blocking platelet aggregation induced by collagen patients or normal 
volunteers. 

The pathogensis of bleeding in von Willebrandt's disease, a heredi- 
tary bleeding disorder, is complex and incompletely understood. In- 
vestigators at the White River Junction, Yt. YA Hospital, found 
that patients with this disorder have fibroblasts which, grown in 
tissue culture, are deficient in tissue factor, a coagulation factor. This 
factor is employed in routine laboratory assays of coagulation. Fibro- 
blasts from normal persons or persons with other known hereditary 
bleeding disorders had normal tissue factor activity. 

Leukocytes are known to be a source of the tissue factor. When 
endotoxin, a product of certain types of bacteria, interacts with 
leukocytes tissue factor is produced. The presence of platelets, platelet 
membranes or granules prepared from platelets stimulates tissue 
factor release from white blood cells by endotoxin. YA investigators 
at the YA Hospital, Bronx. X.Y.. suggested that in sepsis these three 
factors (leukocytes, platelets and endotoxin) cause the disseminated 
intravascular coagulation that frequently contributes to the death of 
these patients. 

Patients requiring surgery may have an inability to control bleed- 
ing discovered through preoperative tests of bleeding time and platelet 
count. Normally platelets release a blood-clotting substance and them- 
selves help close any vascular opening through which blood escapes. 
A platelet transfusion in which only the blood type of the donor is 
matched with that of the recipient often fails to stop the bleeding 
because the platelets are rapidly destroyed by antibodies in the re- 
cipient. Platelet transfusions from brothers and sisters suggested that 
histocompatibilitv was the problem. The body's immune system will 
destroy, if possible, any tissue or particle which does not have an 
inherited pattern. This individual pattern includes a major locus of 



38 

antigens — Histocompatibility Locus A (HL-A) and other minor 
loci. For platelet transfusions, the VA investigators at the Chicago 
(Res.), 111., VA Hospital found that when the HL-A of donor and 
recipient match platelets survived longer in the recipient and more 
effectively prevented bleeding during and after surgery. The investi- 
gators used available relatives to obtain HL-A matches: otherwise, 
computer-assisted-determinations selected matched donors from vol- 
unteers among the hospital personnel. 

Immunology 

Immunologic aspects of connective tissue diseases 

Two connective tissue diseases under study are systemic lupus 
erythematosus (SLE) and Sjogren's syndrome. Research at the 
Dallas, Texas, VA Hospital has shown that the deposition of im- 
munglobulin at the dermal-epidermal junction of human skin cor- 
related well with the deposition of immunoglobulins in the glomerulus 
of the kidney. 

During the past year these findings have also been demonstrated 
in hybrid mice, a rather striking model of human SLE. Demon- 
stration of this finding should permit further analysis of the phe- 
nomenon to determine its prognostic and clinical significance. At the 
Denver, Colo., VA Hospital, specific removal of antibody to DXA 
with an insoluble DNA-cellulose immunoabsorbent was achieved in 
an in vitro system which could be adapted for in vivo extracorporeal 
removal of such antibodies. The DNA-antiDXA sj^stem is the most 
important type of immune complex contributing to serious renal 
disease in SLE. 

At the Buffalo, N.Y., VA Hospital, a new RNAprotein antigen of 
cytoplasmic origin was found to react specifically with antibodies in 
the sera of patients with SLE and also in the sera of patients with 
Sjogren's syndrome (25 percent). A few patients with such antibodies 
to cytoplasmic RXAprotein, but without antinuclear factors, have the 
clinical picture of SLE. They may represent part of the spectrum of 
SLE overlooked because they lack antinuclear antibodies throughout 
their course. 

At the San Francisco. Calif.. VA Hospital, B2 microglobulin, a 
small polypeptide which is a part of membrane of peripheral blood 
lymphocytes, was increased in the saliva of patients with Sjogren's 
Syndrome and in the synovial fluid of patients with rheumatoid 
arthritis. The level of B2 microglobulin in the saliva seems to cor- 
relate with the level of disease activity and might guide therapy. 
There are no other laboratory parameters at present that correlate 
with disease 4 activity and a search for viruses in labial biopsy speci- 
mens from Sjogren's patients yielded no positive results. 

Immunological aspects of pulmonary disease 

Also at the San Francisco VA Hospital, basic studies are underway 
to characterize the immunological features of immune responses in the 
lungs. An animal model was developed and the lymphocytes in the 
respiratory traqt have been characterized and compared to systemic 
lymphocytes. Immunization by aerosol was compared to systemic im- 
munization and the relative distribution of sensitized cells after ex- 



39 

posure by the two routes has been ascertained. These studies show 
that the lung is immunologically active, has specific features in terms 
of the kinds of cells generated (lgM and lgG but not IgA cells to 
sheep erythrocytes), can participate in immunization in a primary 
fashion and can maintain specific functional characteristics. 

At the Wood, Wise, VA Hospital, there have been studies of various 
types of hypersensitivity pneumonitis, including Pigeon breeders 
disease. This inflammatory lung disease seems to have two compo- 
nents: one, an immune complex disorder and the second, a cell 
mediated process with both antibody and cells directed toward pigeon 
serum proteins and other avian proteins. Techniques for the assessing 
of precipitins and cell -mediated responses to these antigens have been 
developed and refined to support this interpretation. 

A case of allergic pulmonary aspergillosis has been studied and the 
report suggests that this disease, which is not rare in Great Britain, 
may be a problem in the USA. 

An epidemiologic study relates hypersensitivity peneumonitis to 
thermophilic fungi. More of such organisms can be cultured from the 
homes of patients and more patients than controls have precipitating 
antibodies to antigens from the organism. Finally, patients with in- 
flammatory pulmonary disease which developed during treatment with 
nitrofurantin provided evidence for lymphocyte reactivity against 
nitrofurantin. Cellular hypersensitivity to nitrofurantin may play 
some role in the pathogenesis of pulmonary inflammatory disease. 

Immunological aspects of malignancy 

Animal models of malignancy have been studied with respect to 
specific immunological features. At the Sepulveda, Calif., VA Hos- 
pital, murine fibrosarcomas were treated by immunization with BCG, 
a tuberculosis-like organism which is known to enhance cell -mediated 
immunity and/or neuraminidase, an enzyme which removes sialic 
acid from molecules bearing it. Some regimens could enhance growth 
or cause regression depending on the specific tumor and the timing of 
the therapy. At the San Francisco, Calif., VA Hospital, it was shown, 
using autoantibodies against murine EL-4 lymphoma and P-815 
mastocytoma cells, that cytotoxic complement-fixing antibodies could 
be converted to blocking antibodies by lysozomal enzymes from the 
tumors themselves. Such effects in vivo could contribute to enhanced 
tumor growth. 

A report from the Chicago (WS) 111., VA Hospital illustrates how 
cells can be recruited into a malignant clone by means of its surface 
immunoglobulin, a mechanism not requiring cell division. In the plas- 
macytoma system, RNA extracts from tumor cells can cause the ap- 
pearance of plasmacytoma lg on the surface of normal lymphocytes. 
At the San Francisco VA Hospital, lymphomas which arise in hybrid 
mice have been characterized as B cell tumors. Such lymphomas arise 
in one-third of the mice who survive longer than 12 months. 

Basic Investigations of immunochemistry, complement, and all 
mediated mechanisms 

At the VA Hospital, Iowa City, la., specific antibodies, purified by 
isolectric focusing techniques and the ability of fragments of such 
antibodies to bind antigen, is under investigation. At the Wood, Wise, 



40 

VA Hospital, studies suggest that the alternate pathway of comple- 
ment activation plays a role in releasing histamine from the leuko- 
cytes of allergic individuals. Studies at the Nashville, Tenn., VA Hos- 
pital, show that the alternate pathway can induce platelet aggregation, 
a phenomenon which may underlie certain inflammatory reactions. At 
the Houston, Texas, VA Hospital, research is in progress on the 
regulation of cell-mediated immune responses and the short-term 
effects of corticosteroids on immunoglobulin synthesis. At Nashville 
a substance released from lymphocytes which promotes the appear- 
ance of eosinophils has been partially characterized. At the VA Hos- 
pital, Buffalo, N.Y., research on the characteristics of antibodies that 
distinguish single amino acid differences in proteins reveal them to 
be quite homogeneous, resembling myeloma proteins. 

Infectious diseases 

A broad, intensive research program in infectious diseases continues 
in the VA involving most hospitals in the system and contributing 
significantly to better patient care. This type of investigation bears on 
such other medical problems as cancer, heart disease, emphysema, 
collagen diseases, complications of narcotic usage and infections in 
travelers. In addition to its clinical application, it advances knowl- 
edge in basic fields such as microbiology and immunology. 

Bacterial infections 

A cooperative study reported this past year analyzed data on 80 
strains of slow-growing organisms related to the tubercle bacillus 
using a numerical taxonomic method. Five distinct species were rec- 
ognized. The international research group embraced 18 institutions 
including the VA Hospital, Long Beach, Calif. A group at the VA 
Hospital, Wood, Wise, is studying glycoprotein biosynthesis in 
another type of mycobaeterium. The morphology of a bacterial virus 
(bacteriophage) active against still another mycobacterium was 
studied by investigators at the VA Hospital, Little Rock, Ark. 

At VA Wadsworfch Hospital Center. Los Angeles, Calif., investiga- 
tors found that anaerobic bacteria vary greatly in their sensitivity to 
oxygen, some tolerating as much as 10 percent oxygen in the atmos- 
phere and others requiring 0.4 percent or less. Survival in air, between 
transfers, was relatively long indicating that simplified procedures 
may be effective in eulturing these bacteria from patients. 

Investigators at the VA Hospital. Iowa City, Iowa, studied the 
metabolism of a type of Pseudomonas, sometimes found in infection-, 
which is able to grow at 0° C. One critical enzyme in this organism is 
active at very low temperatures. 

So-called L forms of bacteria, which have no or deficient cell walls 
have been suspected of being responsible for the chronicity of certain 
infections; exacerbations may relate to reversion to the original bac- 
terial form. While the sigificance of this phenomenon in human disease 
remains uncertain, work done in collaboration with the VA Hospital. 
New Orleans, La., demonstrated that the process of microbial per- 
■!<•<> as L forms and the reversion can take 1 place in human cmbrv- 
kidney cells in ti Bue culture. Several VA facilities — Iowa City, 
ia. Chicago, aid Long Beach, have investigated the mechan- 
isms of diarrhea production in various dysenteries or diarrheal states. 



41 

Enhanced small intestinal loss of fluid and electrolytes is mediated by 
the adenyl cyclase-cyclic AMP system in cholera and in toxigenic E, 
coll diarrhea, an important type of travelers diarrhea and a cause of 
other forms of gastroenteritis in adults and babies, the mechanism 
was demonstrated in various test systems including tissue cultures of 
adrenal tumor cells. 

The toxins elevate intracellular levels of cyclic AMP in virtually all 
mammalian tissues and are therefore potentially valuable tools for 
studying the molecular events of all related cellular phenomena. These 
include the effects of hormones at the cellular level, cell growth and 
division, and the relationship between prostaglandin and adenylate 
cyclase. A surface-active antibiotic, polymyxin, has been utilized to 
release from E. coll a certain type of diarrhea-producing toxin so that 
it can be better characterized. 

Antibodies can be produced against at least one type of toxin pro- 
duced by E. coli and these cross-react with cholera toxin. Toxin assay 
procedures permit serologic types of epidemiologic investigations and 
the evalaution of vaccines or toxoids. Other types of diarrhea-related 
toxins, namely those produced by the dysentery bacillus and by Clos- 
tridium perfrpngens which causes food-poisoning apparently have a 
mechanism of action which differs from the toxins. 

A clinical study by a group of VA investigators from Sepulveda, 
Calif., documents the frequency with which toxin-producing strains 
of E. coll may cause traveler's diarrhea, a poorly understood entity. 
About 70 percent of such illness in a group of U.S. students traveling 
in Mexico was associated with these E. Coli. 

The pneumococcus, a type of streptococcus, is still an important 
cause of pneumonia., especially among the aged. The organisms may. in 
the course of pneumonia, cause bacteremia or blood-poisoning and 
other serious complications so that this illness has a mortality of 28 
percent despite effective antibiotics, according to work done at the VA 
Hospital, Chicago (WS), 111. 

VA investigators are active in the area of bacteriologic diagnostic 
techniques in infectious disease practice. At VA Hospital, Long 
Beach, Calif., as part of an International Working Group on Myco- 
bacterial Taxonomy, investigators evaluated techniques for species 
identification in the complex group of organisms producing tubercu- 
losis and related diseases; several were highly reproducible. 

Investigators at VA Wadsworth Hospital Center, Los Angeles, 
Calif., have determined the validity of three subgroups of Bacteroides 
rrielaninogenicus, have compared three procedures for biochemical 
testing of anaerobic bacteria and have found simple procedures to 
be suitable for identification. They have summarized the use of gas 
chromatography for the detection and identification of anaerobic 
bacteria. At Sepulveda. Calif.. VA researchers have used gas chro- 
matography for presumptive detection of botulism-causing organisms 
in spoiled food. 

A VA group at Wadsworth has developed and evaluated a mem- 
brane filter procedure for the rapid detection and identification of 
bacteria in the blood stream. This offers promise of permitting ear- 
lier and more effective therapy in blood-poisoning, still one of the 
most serious of infectious diseases. The value and pitfalls of certain 
blood tests for antibody detection and of skin tests in the diagnosis 



42 

of infections have been evaluated by VA researchers at Richmond, 
Va.. and at Albuquerque, X. Mex. 

Clinical studies of infectious diseases in the VA system have in- 
volved collaboration between the groups at Sepulveda and "Wads- 
worth Hospital Center, Calif. They documented the role of anaerobic 
bacteria in a variety of pulmonary infections including aspiration 
pneumonia, lung abscess, empyema and others. They stress the spe- 
cial techniques required to avoid overlooking these important patho- 
gens since many infections have been attributed to other organisms 
and therapy has not uncommonly been misdirected as a result. Other 
workers at Wadsworth studied the role of anaerobic bacteria in neo- 
natal bacteremia and in subdural empyema. 

At Oklahoma City, Okla., VA workers, in collaboration with Viet- 
namese investigators, detected significant (46 percent) resistance of 
typhoid bacilli to chloramphenicol, formerly the drug of choice, in 
Saigon and determined that ampicillin and cotrimoxazole were sat- 
isfactory alternatives. 

Infections due to microorganisms other than bacteria 

So-called "slow viruses"' produce several chronic neurologic dis- 
eases in animals and such organisms may cause similar human dis- 
eases. A VA group at San Francisco, Calif., has been involved in a 
series of basic investigations of such viruses involving analysis of 
their structural polypeptides, comparison of EXA with that from a 
tumor virus and, investigation of the mechanism of nucleic acid syn- 
thesis and study of its products. 

Fundamental studies of a natural infection with two different viruses 
in single cells in a tissue culture line have been reported from the 
VA Hospital, West Haven. Conn. Latent herpes virus was recov- 
ered from the spinal g&nglia of mice without illness by VA investi- 
gators at Chicago (WS). 111. In young adults this prevented clinical 
illness due to one of the common cold viruses by means of a topical 
interferon inducer administered as nose drops for two days, begin- 
ning one day before challenge with the virus. Other investigators at 
the same VA facility found evidence that certain adenoviruses play 
a role in some cases of acute hemorrhagic cystitis and detected the 
presence of one of the viruses causing infectious hepatitis among 
natives in remote parts of Africa. 

Parasitic infestations continue to attract the interest of VA clini- 
cians and researchers. An investigation of the effect of chloroquine on 
the maturation of certain malarial parasites in man was reported from 
the VA Hospital, Towa City. Towa. 

A VA investigator at New Orleans, La., has confirmed that coun- 
teiiininnnoelect rophoresis can be utilized in a relatively rapid, depend- 
able serologic test for amebiasis. A serologic test for the diagnosis of 
\ isceial larva migrans! a serious worm infestation, has been described 
as well as evidence for a parasitic fluke infection in prehistoric man. 

VA investigators at Long Beach, Calif, contributed to the standard- 
ization of reagents and methods in medical mycology. Infectious par- 
ticles called xenosonies were reported to occur in unicellular animals. 
These self-repiicating particles, a single one of which is infectious to 
certain sail water protozoa, are larger than viruses, contain large 
amounts of DXA and are unique in that they contain multiple copies 
of complete genetic information. 



43 

Host defense mechanisms against infection 

Much attention is being 1 given to host defense mechanisms in infec- 
tious diseases. Cell -media ted immunity in relation to various viral in- 
fections is under investigation at VA Hospitals in Houston, Texas. 
Cincinnati, Ohio, and Brockton. Mass. In infectious mononucleosis, 
cutaneous energy may occur along with hypo-responsiveness of lym- 
phocytes or macrophage precursors in the blood and with transient 
but marked decrease in the number of white blood cells. 

In rubella infection, skin hypersensitivity was markedly impaired 
at the height of the illness but lymphocyte function was otherwise 
normal. Mild viral respiratory infections, however, had no influence 
at all on cell-mediated immunity. An in vitro assay of cell-mediated 
immunity to measles virus was described, permitting an explanation 
of abnormal host reactivity which may predispose to subacute scleros- 
ing panencephalitis. 

Bdcteroides fragilis is the most commonly encountered anaerobic 
pathogen. The most common subspecies in clinical infection were 
shown by investigators at Wadsworth Hospital Center. Los Angeles, 
Calif., to be resistant to normal serum factors which kill strains of 
fecal flora. Phagocytosis and killing of anaerobic bacteria by human 
leukocytes was also noted. Estrogens have been reported to enhance 
phagocytic activity in animals. 

At the VA Hospital, Oklahoma City, Okla.. estrogen administered 
orally to patients with meningitis due to crypt ococcus resulted in mod- 
erate to marked stimulation of phagocytosis and disappearance of 
circulating capsular material from the fungus. 

VA investigators at Pittsburgh, Pa., demonstrated that antigen 
stimulation of leukocytes enhances release of a prostaglandin. Fur- 
ther work must determine the mechanism of this phenomenon and 
its biologic significance. 

Therapy and prophylaxis 

A standardized procedure for determining suspeetibility of slow- 
growing anaerobes to antimicrobial agents by the simple disc tech- 
nique was described. VA investigators at Wadsworth and Sepulveda, 
Calif., have reported independently and jointly on the suspeetibility 
of anaerobic bacteria to various penicillins and cephalosporins and 
on the susceptibility to various antimicrobial agents of Clostridium 
ramosum, a common but often overlooked pathogen. 

A pharmacologic and clinical investigation of intramuscular and 
intrathecal gentamicin for meningitis due to Gram-negative bacilli 
was reported by investigators at the VA Hospital. New York, X.Y. 
In experimental murine coccidioidomycosis, tetracycline administered 
with amphotericin significantly reduced the amount of more toxic 
agent required for a good response. Protective immunity against 
amebiasis was produced in guinea pigs by a researcher at the VA 
Hospital, Xew Orleans. La. 

Allergy 

Studies on asthma in spontaneously ragweed-sensitive animals and 
its response to prednisone were reported from Wood. Wis.. VA Hos- 
pital. The steroid completely prevented the asthma during and for 
three months after cessation of treatment. Clinical studies of alpha 
and beta adrenergic imbalance in intrinsic intolerance rhinitis and 



44 

asthma wore carried out at the VA Hospital, Chicago (WS), 111. The 
same workers studied the risks of using aspirin as an anti-hemostatic 
agent in hypersensitive patients and proposed a method to reduce 
the risks. Studies of immunologic tolerance in animals have been re- 
ported and a role for regional lymph nodes in tolerance production 
is postulated. 

Mental health and behavioral sciences 

Psychotherapy is the most expensive treatment employed with 
psychiatric patients. Yet its efficacy is uncertain, the specific effects 
of different techniques remains unknown and the best way to select 
particular treatments is undetermined. VA investigators attack these 
problems employing controlled methods of evaluation. 

Kind-firmness attitude therapy as a treatment for depression con- 
sists of prolonged, ungratifying work designed to prod the patient 
toward assertive expressions of anger, thus relieving the depression. 
A research team at the VA Hospital. Tuscaloosa, Alabama, compared 
kind-firmness and conventional therapy employing active friendli- 
ness and anti-depressant medication. Both treatments reduced anxiety 
about equally well among neurotics but kind-firmness was more effec- 
tive in alleviating depression. Psychotics treated with this approach 
showed significant reduction in tension but no decrease in anxietv- 
proneness while psychotics treated on the conventional program 
demonstrated the opposite pattern. 

Another radical treatment, implosive therapy, requires the patient 
to imagine his worst fears in an exaggerated state so that he can 
realize their irrationality and rid himself of them. An investigator 
at the VA Hospital, Iowa City, Iowa, compared the five-year re- 
hospital ization rates of patients randomly assigned to implosive 
therapy and traditional milieu treatment. The former had a signifi- 
cantly lower ^hospitalization rate over that period. 

Another unconventional treatment uses volunteers to serve as "big 
brothers" to chronic patients leaving psychiatric hospitals. A VA 
controlled study at Bedford, Mass., Tuscaloosa, Ala.. Marion, Ind. 
and St. Cloud, Minn., compared the progress of patients released on 
such a program to that of a group not assigned to volunteers. The 
two groups had the same amount of change on a wide variety of 
adjustment and recidivism measures during the ensuing 1^ months. 
The outpatient volunteers did not help psychiatric patients and the 
program was discontinued. 

Depression is a particularly common psychiatric problem endanger- 
ing society's menial health and its economic well-being. Researchers 
in 18 hospitals cooperated in comparing the prophylactic effective- 
of the two major anti-depressant dings — lithium carbonate and 
imipramine — in discharged patients. Both drugs prevented relapse 
when compared to placebo treatment. Unipolar depressives responded 
equally well to both drugs; manic-depressives improved more with 
lithium. 

VA investigators also made substantial progress on psychological 

problems this year. At St. Cloud, Minn., four studies compared 

the abilities of 15 short intelligence tests to predict Wechsler Adult 



45 

Intelligence Scale scores. Most institutions rely on short group intel- 
ligence^ tests rather than the better but lengthier and more costly 
Wechsler Adult Intelligence Scales. The VA research provides the 
first comprehensive comparison of short tests to the Wechsler scales. 
Two short tests — the Henmon-Xelson and the Test of Educational 
Ability — were significantly better than most of the more familiar, 
commonly used ones. 

Most ps3'chologieal brain-damage tests cannot separate brain-dam- 
aged persons from other psychiatric patients. This has caused func- 
tional psychiatric patients to be misdiagnosed as brain-damaged and 
has led VA investigators to develop a scale derived from the Minnesota 
Multiphasic Personality Inventory for separating brain-damaged 
from schizophrenic groups. During the past year. VA investigators at 
Brecksville. Ohio and Topeka, Kansas have verified this scalers ability 
to make the separation. 

The Brecksville group also provided evidence that the Minnesota- 
Precepto Diagnostic test, a copying task, may distinguish organic 
brain damage from schizophrenia if administered on special ''Back- 
ground Interference" paper. The paper resembles an assembled 
iigsaw puzzle and tends to interfere with the performance of brain- 
damaged patients more than with that of schizophrenics. 

Neither the causes nor the precise nature of the cognitive deficits 
in major psychiatric illnesses are well understood. One theory of 
schizophrenia maintains that the pathological symptoms represent 
little more than attempts to obtain financial benefits and a non- 
demanding environment by appearing helpless. A VA study, however, 
indicates that schizophrenics actually have less ability to manage the 
impressions they make on others than do other psychiatric and non- 
psychiatric groups. These results undermine the theory. 

A team at the VA Hospital. San Diego. Calif., has developed a ques- 
tionnaire to assess loss of remote memory based on the ability to rec- 
ognize the name- of past television programs, race horses and news 
events. With it the team has made the first controlled studies of the 
effects of electric shock therapy (ECT) on memory for remote events. 
Five ECTs will produce retrograde amnesia going back five to eight 
years but this amnesia is reduced by 50 percent within two weeks. In 
a study of remote memory under normal conditions, the number of 
memory traces decreased with time, but the resistance of the surviving 
traces to disruption hardened over the years. Very long-term memory 
was less often destroyed by ECT and traces older than 8 years per- 
sisted. Memories intact at that time were likely to last indefinitely. 

Few non-invasive techniques can evaluate the brain activity of hu- 
man subjects. One method involves averaging the electroencephalo- 
graphic (EEG) activity as recorded from the scalp after repeated 
stimuli. The EEG activity which is unrelated to the stimulus varies 
randomly and its average tends toward zero; electrical potentials 
("evoked responses") related to the stimuli remain evident and mea- 
surable. The responses elicited by auditory, visual and somatic stimuli 
have different distinctive characteristics. 

One basic question is the effect of age on evoked responses. VA 
investigators at Salt Lake City. Utah, have described visual, auditory 
and somatosensory responses in 225 normal subjects between the 



46 

of 4 and 16 years and in an additional 200 subjects between the ages 
of IT and 86 years. They demonstrated maturational changes in the 
younger groups and effects of aging in the older subjects. The changes 
with age were particularly prominent for visual stimuli and are the 
most pronounced age-related changes in any measure of waking 
brain activity investigated thus far. The Salt Lake City investigators 
have also pioneered in the application of evoked response techniques to 
patients with cerebral pathology, including those with Down's syn- 
drome and centrencephalic epilepsy. They are currently assessing the 
value of responses as indicators of brain death. 

Another non-invasive measure of brain activity is the sleep EEG 
which is also sensitive to age and to the effects of psychoactive drugs. 
A VA investigator in San Francisco, Calif., in collaboration with re- 
searchers at the University of California, found substantial effects of 
large doses of THC. the active ingredient of marijuana, on the sleep 
EEG. These are the most clear-cut effects of THC on human brain 
activity demonstrated thus far, but their significance is unknown. 

VA investigators continue to contribute substantially to the basic 
and clinical understanding of drugs used in the treatment of major 
mental illnesses. VA invest igators at Palo Alto, Calif., compared sys- 
tematically the efficacy of 3 different chemical classes of anti-schizo- 
phrenic agents. They found no differences in the overall effectiveness 
in 320 newly-hospitalized schizophrenic patients although piperazines 
were somewhat more effective in older patients with core schizo- 
phrenic symptoms. The investigators concluded that differences in 
response to anti-schizophrenic drugs more likely reflect idiosyncratic 
differences in drug absorption or metabolism than major pharma- 
cologic differences. 

Lithium salts, widely used in the treament and prophylaxis of 
manic-depressive illness, were evaluated in a VA-NIMH collaborative 
study of prophylactic lithium therapy in 205 patients with bipolar 
manic-depressive illness. Lithium was superior to placebo for prevent- 
ing new attacks. A poor response was associated with a recent history 
of frequent episodes of illness and with a previous failure of lithium 
therapy. 

VA investigators in Philadelphia, Pa., investigated the (^ffef'ts of 
lithium on EEG sleep patterns of hospitalized depressed patients. 
Lithium reduced awakenings increasing stage 4 sleep while decreasing 
the duration of rapid eye movement sleep and the intensity of eye 
movements during this phase. The Philadelphia team studied the 
effects of two amino acid precursors, 1-dopa and 1-tryptophone, on 
ressive symptoms under double-blind conditions to evaluate the 
catecholamine hypothesis of affective disorders. There were no effects 
suggesting that the catecholamine hypothesis, at least in its simple 
form, is insufficient. 

Nephrology 

Prevention of kidney disease 

Endogenous or exogenous compounds that may alter renal function 
of induce disease must be studied in animal models of human disease. 
A' A Investigators at Los Angeles. California developed a model of 
urate nephropathy by feeding oxonic acid, a known inhibitor of 



47 

uricase, to rats. Urate-blockade nephropathy results when the animals 
are fed oxonic acid for three weeks. One year's administration causes 
chronic interstitial nephritis resembling gouty nephropathy. 

Employing a similar animal model investigators at the VA Hos- 
pital, Durham. X.C, decreased renal function within one week by 
giving oxonic acid alone or in combination with high uric acid feed- 
ings. The lesion may be due in part to precipitation of uric acid in the 
collecting ducts and seems more severe in the deeper nephrons and with 
the combined treatment. 

VA investigators in Houston. Texas showed that intravenous man- 
nitol protects renal function in renal transplant recipients who are 
given the nephrotoxic agent amphotericin B for systemic fungal 
infections. Bicarbonate given in addition to mannitol helps circum- 
vent both postulated mechanisms of renal injury — the vascular effect 
and the cellular injury. 

According to investigators at the VA Hospital, Iowa City, Iowa, 
decreased clearance of paraaminohippurate (PAH) may not in fact 
reflect decreased renal blood flow dining anesthesia. Some general 
anesthetics, such as methoxyflurane, decease the transport of PAH in 
rabbit kidney slices. 

Investigators at the VA Hospital. Palo Alto, Calif., studying the 
nephrotoxocity associated with anethestic agents have demonstrated 
that other 'general anesthetics (enflnrane). which like methoxyfiuorane 
are partially metabolized to fluoride, cause polyuria and vasopressin- 
resistant renal dysfunction in a special strain of rats. These animals 
break down fluorinated compounds in a fashion similar to man and 
the results have led to a clinical evaluation of fluorinated anesthetics. 

Nephropathy in drug addicts was studied at the VA Hospital, Hous- 
ton. Texas. The nephrotic syndrome was the presenting feature in all 
six patients and two progressed to terminal renal failure in less than 
a year. The renal damage appears to be secondary to immune-complex 
deposition with interstitial swelling, mononuclear infiltration and 
tubular dilatation signaling rapid deterioration of renal function and 
a grave prognosis ; their absence indicates a prolonged, indolent course. 

Treatment of kidney disease 

A new test developed at the VA Hospital, Dallas, Texas, provides a 
sensitive and reliable noninvasive means of differentiating infection of 
the upper urinary tract from that of the lower tract. It consists of 
detecting the presence of antibody-coated bacteria in the urinary sedi- 
ment, their presence correlating closely with upper urinary tract in- 
fection. This technique is applicable to the hospital diagnostic micro- 
biology laboratory and results can be available early in the patient's 
management when such information is most helpful. 

The clinical efficacy, tolerance, and pharmacokinetics of the new 
amino-glycoside antibiotic, sisomicin, were studied in elderly male 
patients sufferino- from complicated urinary tract infections at the VA 
Hosivtal. Madison. Wisconsin. Sisomicin was effective against .^ram- 
negative organisms and was well tolerated but did not offer major 
advantages in comparison to gentamicin. 

Investigators at the VA Hospital. Nashville, Tennessee, reported a 
new method for achieving a desired mean serum penicillin G concen- 



48 

t rat ion in patients with renal failure. The method, based on the linear 
relations between the total plasma clearance of penicillin G and of 
endogenous creatinine, allows minimal risk of both undertreatment and 
drug toxicity. Investigators at the VA Hospital, Bronx, New York, 
also recommended that the parenteral dose of the antibiotic clindamycin 
phosphate be reduced by at least one-half in patients with chronic renal 
failure. 

Because existing symptomatic therapy for clinical hypercalcemia is 
unsatisfactory, investigators at the VA Hospital, Washington, D.C. 
examined the acute and chronic effects of the diuretic agent, furos- 
emide, on hypercalcemia produced in animals by clacifero! plus cal- 
cium chloride. Furosemide effectively lowered elevated serum calcium 
concentration by increasing glomerular filtration and depressing tubu- 
lar reabsorrtion of calcium vhen depletion of extracellular fluid vol- 
ume or dehydration is prevented during the course of the diuresis. 

Treatment of gram-negative urinary tract infections in patients with 
urological abnormalities — a particularly common and severe problem 
at VA clinical facilities — interests VA investigators. At the VA Hospi- 
tal, Houston, Texas, blocking urease production by means of acetohv- 
droxamic acid was shown to decrease the invasiveness of Proteus in- 
fections and to enhance the antibacterial effect of methenamine. 

Dialysis, transplantation, and treatment of uremia 

At the VA Hospital in Richmond, Virginia, the urinary excretion 
of sodium and water was investigated in patients with chronic end- 
stage renal disease in an attempt to dissociate and examine separately 
the effects of solute load (urea) and extracellular fluid volume 
expansion. 

The overall excretion by sodium and water by any one patient is 
directly influenced by several factors including solute load, the degree 
of extracellular fluid volume and the glomerular filtration rate. Maxi- 
mal excretion of sodium and water by the patient with chronic renal 
insufficiency can be obtained only at the expense of both marked 
azotemia and extracellular fluid volume expansion. Furthermore, a 
major reduction in extracellular fluid volume in the patient with 
chronic renal failure will almost certainly lead to a fall in blood 
pressure and glomerular filtration rate with further reduction in so- 
dium excretion. 

At the VA Hospital, Denver Colorado, post mortem tissue analysis 
of 27 patients maintained on hemodialysis for 2 to 75 months revealed 
significant potassium depletion in 58 percent of the patients, primarily 
in skeletal muscle, myocardium and brain potassium depletion was 
observed with all dialysate potassium concentrations hut was greatest 
in patients dialyzed against potassium-free bat lis. Maintenance of nor- 
mal intracellular potassium stores may require stricter metabolic 
control in the inter-dia lytic period as well as elimination of potassium- 
free dialysates. The same investigators concluded that changes in 
muscle magnesium reflect changes in total body potassium and are not 
did indicator of total body magnesium in patients with chronic 
renal failure. 

Electroencephalographic changes and various central nervous sys- 
tem abnormalities occur in patients with uremia. Investigators at the 
Wadsworth YA Hospital, Los Angeles, California found a significant 



49 

increase of brain calcium content in acutely uremic animals. This 
phenomenon was prevented by parathyroidectomy but occurred after 
the administration of parathydroid extract both to normal and uremic 
animals previously subjected to thyroparathyroidectomy. The electro- 
encephalographs changes found in animals with acute renal failure 
require the presence of excess parathyroid hormone in blood, and may 
be related to the observed changes in the brain content of calcium. 

The question of why toxic symptoms appear with altered nitrogen 
metabolism in uremia remains unanswered. Investigators at the Wads- 
worth VA Hospital. Los Angeles. California showed changes in amine 
oxidase activity in the blood of uremic patients and in various tissues 
of chronically uremic animals, suggesting that the catabolism of 
amines in uremia may be altered with unknown metabolic consequences. 

The metabolic processes by which urea is synthesized in chronic 
uremia have received little attention. Researchers at the Wadsworth 
VA Hospital, Los Angeles, California have studied the urea cycle in 
uremia by measuring the plasma and tissue levels of the amino acids 
arising from or directly related to the cycle in patients with renal 
failure and in experimental uremic animals. Similar concentrations 
of aspartic acid and arginine occurred in control and uremic subjects 
while both ornithine and citrulline were elevated in uremic patients. 

The anemia of chronic renal failure is important because it reduces 
the supply of oxygen to the tissues. To compensate, patients reduce 
the affinity of hemoglobin for oxygen, a process mediated by the red 
blood cell enzyme 2,3-DPG. At the VA Hospital, Indianapolis, In- 
diana, the in vivo P 50 decreased significantly during hemodialysis, a 
fall entirely attributable to the rise in red blood cell pH by the Bohr 
effect. The decrease of in vivo P 50 during hemodialysis may transiently 
impair tissue oxygen delivery in uremics and marked increase of the 
pH should be minimized. 

Occasionally, patients with mild to moderate chronic renal failure 
have elevated serum potassium concentration in disproportion to the 
level of impairment of glomerular filtration rate. They usually have 
hyporeninemia, hypoaldosteronism and hyperchloremic acidosis. The 
role of mineralocorticoid deficiency in this newly recognized syndrome 
in uremic patients was investigated at the VA Hospital. Miami, 
Florida. The syndrome of hyperchloremic acidosis with hyperkalemia 
and mild renal insufficiently was usually associated with hypoaldoste- 
ronism and the hyperkalemia was rapidly corrected by mineralocor- 
ticoid treatment. The mild hydrogen ion secretory defect in some 
patients may be due to intrinsic tubular damage since mineralocorti- 
coid therapy did not correct it. Patients with normal renal function 
and mineralocorticoid deficiency in Addison V disease or bilateral 
adrenalectomy exhibit only moderately impaired acid excretion and a 
normal capacity to excrete hydrogen ion. 

Much research in nephrology concerns dialysis and transplantation 
with the VA developing these therapeutic modalities for end-stage 
renal disease patients. Investigators at the VA Hospital. Columbia. 
Missouri, continued work on the kinetics of coil dialyzers demonstrat- 
ing that ultrafiltration rate markedly influences the dialysance of 
larger molecular weight solutes in coil dialysis. The same investigators 
studied the extent and complexity of blood-membrane interactions 



50 

during clinical dialysis. Many blood components (leukocytes, plate- 
lets, fibrin-like strands and many free-cell organelles) were deposited 
in the coil membranes and the deposition increased directly with the 
blood perfusion time in spite of using heparin with the intermittent 
intravenous technique. 

It is difficult to determine the optimal dietary intake of vitamins in 
uremia because metabolism is altered and because vitamin losses during 
dialysis are not well-defined. Investigators at the VA Hospital, 
TVadsworth, Los Angeles, California, calculated the vitamin content 
of diets prescribed for chronically uremic patients and subject? under- 
going dialysis. For thiamine, niacin, panthotenic acid and biotin, a 
supplement equivalent to the recommended daily allowance for normal 
subjects is sufficient. For folic acid vitamin B 6 and ascorbic acid die- 
tary supplementation is needed. Excessive consumption of vitamins, 
particularly of the fat-soluble vitamins, in uremia may be disadvan- 
tageous. 

The level of erythrocyte transketolase activity (ETKA) might 
correlate with the presence of uremic neuropathy but studies at the 
VA Hospital, Nashville, Tennessee showed that ETKA is unrelated 
to the peripheral neuropathy in uremia. Hemodialysis did not affect 
ETKA in uremic patients with proved peripheral neuropathy, nor did 
uremic plasma have any inhibitory effect on ETKA in erythrocytes 
from nonuremic patients. 

There is need for sensitive, accurate, and easily performed measure- 
ments to assess the severity of uremic toxicity. Perception of short time 
intervals have been suggested as one such measurement. At the AVads- 
worth VA Hospital, Los Angeles, California, it was shown that, in 
patients on hemodialysis, short time interval perception is inversely 
related to the length of the interdialytic period, suggesting that this 
index may be inversely related to the severity of uremia. The instru- 
ment employed appears to provide an accurate, sensitive and easily 
administered technique for monitoring uremic toxicity. Investigators 
at the VA Hospital, Denver, Colorado demonstrated that the renin- 
angiotensin system is markedly activated during hyperacute herero- 
graft rejection in a renal xenograft animal model. 

At the VA Hospital, San Francisco, California, studies aimed at 
improving the perfusion systems employed in kidney preservation 
found that eryoprecipitated plasma can be replaced by colloids and 
that phosphate buffers can replace bicarbonate buffers. Cryoprecipita- 
tion. millipore filtration, the need for typed plasma, and the risk of 
virus transmission can be eliminated, as well as the need of adding COg 
to the gassing mixture. I-Cmploying an adequate oxygenator, only am- 
bient air is required for gassing. 

Kidney function in health and disease 

Continuing studies on renal hemodynamics, investigators at the VA 
Hospital, San Francisco, California, examined the influence on the 
glomerular arteriolar resistance resulting from alterations in effective 

blood viscosity and explained t\w tendency for the fraction of the 
plasma actually filtered at the glomeruli to vary directly with hemato- 
crit in anemic and |>ol vcyiemic states in man. 

The same investigators studied the adaptive increase in glomerular 
ultrafiltration rate which occurs in the remaining nephrons when the 



51 

renal mass is reduced. They employed a unique strain of Wistar rats 
with glomeruli located on the kidney surface allowing special micro- 
physiological techniques. The adaptive increase in the glomerular fil- 
tration rate of a single glomerulus results primarily from increases in 
the glomerular plasma flow and transcapillary hydraulic pressure 
difference. 

Investigators at the VA Hospital, Oklahoma City, Oklahoma, 
studied the effects of histamine on the renal circulation. Injection of 
histamine into the renal artery of an animal lowers the renal vascular 
resistance and secondarily increases lymph and urine formation with 
no direct effect on renal vascular permeability. 

At the VA Hospital, Houston, Texas, studies elucidated the factors 
that regulate bicarbonate reabsorption by the kidneys and control the 
acid-base status of the body. Parathyroid hormone acted directly on 
the renal tubules and decreased the reabsorption of bicarbonate. The 
reabsorption of urate by the renal tubules is influenced by the state 
of hydration and the extracellular fluid volume. Although significant 
differences in urate metabolism may exist between an animal and man, 
a similar mechanism may explain the hyperuricemia observed in man 
following chronic usage of diuretics. 

Eenal function after relief of ureteral obstruction in the experi- 
mental animal depends on whether one or both ureters have been ob- 
structed. Investigators at the VA Hospital, Durham, North Carolina, 
used animals with unilateral ureteral obstruction to show that the 
absence of postobstructive diuresis results from marked reduction in 
renal hemodynamics. The filtration distribution becomes severely 
heterogenous with many non-filtering nephrons and a reduced delivery 
of filtrate to the distal parts of the nephron. 

Studies done at the VA Hospital, Iowa City, Iowa, using an isolated 
animal kidney prepartion found that renin depletion impairs the ca- 
pacity of the kidney to autoregulate blood flow and glomerular filtra- 
tion rate. 

The diuretic agent furosemide at large doses may alter the clinical 
course of acute renal failure and this phenomenon was studied at the 
VA Hospital. Miami, Fla. Furosemide was injected into the renal 
artery of six patients 2 to 9 days after the onset of acute renal failure 
but failed to improve renal function. Short-term administration of 
furosemide in large doses did not improve renal hemodynamics or 
alter the clinical course of patients with established acute renal failure. 

Relatively little is known of the forces governing glomerular filtra- 
tion in glomerulonephritis. It was demonstrated at the VA Hospital, 
San Francisco, California that, despite extensive glomerular injury, 
the glomerular filtration of an animal with nephrotoxic serum neph- 
ritis remained normal. Increased transcapillary hydraulic pressure 
difference compensated for the decreased glomerular capillary filtra- 
tion coefficient. 

Hypothyrodism in man is associated with decreased renal hemody- 
namics and sometimes with decreased ability to excrete water and 
hyponatremia. The possibility of altering sodium excertion was 
investigated at the VA Hospital, Miami, Florida, in patients with 
hypothyroidism. Several myxedematous patients were unable to 
achieve sodium balance or did so very slowly when challenged with a 
low sodium intake. 

70-799—76 5 



52 

TThen myxedematous patients were salt loaded their urinary excre- 
tion of sodium matched that of control subjects despite reduced renal 
hemodynamics. However, their capacity to conserve sodium in response 
to stimuli for rapid sodium conservation was diminished. Tubular re- 
absorption of sodium seems decreased in myxedema indicating that 
thyroid hormone influences normal sodium reabsorption. 

Neurology and neurobiology 

Multiple sclerosis 

The incidence of multiple sclerosis varies from one country to 
another, providing clues to the cause of this crippling disease. Thus, 
people moving from an area of high to one of low incidence and vice 
versa may show when and where the disease is acquired. An investi- 
gator at the VA Hospital, Washington, D.C.. reported a preliminary 
study of the prevalence of multiple sclerosis in a population with a 
normally low rate which moved to a region of high prevalence, namely 
Vietnamese moving to Paris. When the prevalence of multiple scle- 
rosis was compared with that of a disease more unifoT'mly prevalent 
amyotrophic lateral sclerosis (ALS), Vietnamese in Paris had com- 
paratively less multiple sclerosis than Frenchmen generally. 

The prevalence of multiple sclerosis in a small area of Komania has 
been investigated by a group at the VA Hospital. Minneapolis, Minn., 
with the finding that there are striking variations from one district to 
another. These variations do not correlate with several variables which 
have been suggested as being important in the disease; notably, cli- 
mate, altitude, urban-rural differences and the level of lead in the 
blood. Another study from the same institution did show a correlation 
between prevalance and the intake of animal fat. A low fat diet might 
impair delayed hypersensitivity mechanisms which may underlie 
multiple sclerosis. 

Research is also being conducted on the chemistry of the nerve myelin 
sheath and on neurochemical changes seen both in natural sclerotic 
plaques and in the animal model of multiple sclerosis, experimental 
allergic encephalomyelitis (E.A.E.). At Palo Alto, Calif., a VA study 
of regional differences iu myelin composition and stability reported 
that differences in stability may be related to the content of the pro- 
teolipid in the myelin and may be a factor in determining the location 
of the lesion in the nervons system. Investigators from the same in- 
stitution also report increases in proteolytic enzyme activity in de- 
mvelinating plaque in E.A.E. These increases and reported increases 
in protein synthesis may be associated with the presence of invading 
mononuclear cells. 

Also reported from Palo Alto is a VA report of the role of anti- 
myelin antibodies in the myelin breakdown seen in E.A.E. A complete 
dissociation occurs between the development of experimental allergic 
encephalomyelitis, the presence of anti-basic protein antibody and the 
occurrence of mvelinat ion inhibition factor, suggesting that myelina- 
tion inhibition factor is not involved in the pathogenesis of experi- 
mental allergic encephalomyelit is. It also argues against a role for 
anti-basic protein antibody as an antimyelin factor /'// ritro. A VA 
study from Boston suggests that humoral antibodies may be re- 



53 

sponsible for some of the early changes in E.A.E. seen by electron 
microscopy, especially the early increase in vascular permeability 
prior to the arrival of immune cells. 

Virus infections 

From the virus laboratory at the VA Hospital. San Francisco, Calif., 
it was reported that herpes simplex Type II virus can be recovered 
from sacral sensory ganglia of persons with no history of symptoma- 
tic disease. Recurrent herpes genitalis thus may be caused by periodic 
migration of the virus down the sensory nerves to the skin ; a sugges- 
tion which may be significant in view of the postulated relationship 
between genital carcinoma and recurrent herpes genitalis. 

San Francisco investigators have also reported on subacute scleros- 
ing panencephalitis (S.S.P.E.), a rare disease, causing intellectual 
deterioration, crippling and death, in children and adolescents. It 
exemplifies a significant new concept in human medicine — that of the 
slow virus infection. An in vivo demonstration in the experimental 
animal of a change in the measles virus from a fully infective par- 
ticle to a defective one infectious only within cells is a new finding. 
This significant change is apparently caused by the host antibody 
response, to be permanent, and may resemble early events in human 
S.S.P.E. 

It may also parallel other slow virus or latent measles infections 
of the nervous system, conditions increasingly suspected of underlying 
many neurological conditions currently regarded as degenerative. Viral 
causes of congenital abnormalities of the nervous system may even 
account for 25— 10 percent of all congenital abnormalities and repre- 
sent, through mental retardation, an immense waste of human and 
economic potential. 

Recovery from stroke 

Damage to the neural tissue, whether due to physical trauma, in- 
fection or interference of its blood supply (stroke) initiates various 
reparative processes. Some of these processes improve the function of 
the nervous system: others, such as brain edema, appear to be dele- 
terious. 

In a series of experiments, investigators at the VA Hospital, Boston. 
Mass., showed that the functional recovery following damage to a re- 
gion of the brain depends on the rate at which the damage occurred. 
In monkeys, the behavioral effects of a single lesion in the frontal 
lobe were more severe and persistent than the effects of a series of 
smaller lesions which actually damaged more tissue in the same area. 
The intact tissue surrounding the lesion seemed to play a critical role 
in recovery, suggesting that it is not true that specific neurological 
functions are rigidly performed by one specific area of the brain. 

In a related development. VA investigators at the VA Hospital, 
Bronx. X.Y.. found that regrowth and sprouting of noradrenergic 
nerve terminals occurs in the region surrounding a lesion in the cere- 
bral cortex. Only 3 hours after the damage was induced in animals, 
signs of this increase of noradrenergic terminal activity could be de- 
tected. This research dealt with the development of seizure activity 
but it also contributed to understanding how functional recovery oc- 
curs. 



54 

Another group of investigators at the VA Hospital, Palo Alto, Calif., 
studied the growth of nerve cells when removed from the cortex of 
newborn animals and grown in tissue culture. Neuronal and archi- 
tectural maturation in several weeks produced specific patterns of 
cellular organization unique to cultures of neocortex and served to dis- 
tingiush these cultures from those of neutral tissue derived from dif- 
ferent neuroanatomical regions. These observations suggest that at 
least some aspects of the structural growth patterns of cells in the cen- 
tral nervous system may be rigidly determined. Other VA research 
at Denver, Colorado, disclosed that a particular type of glial cell hy- 
pertrophies during the chemical injuries to the brain associated with 
hepatic coma. These cells may be critically important in metabolizing 
the excess blood ammonia levels occurring during hepatic coma. 

Sensory and perceptual disorders 

In the area of sensory and perceptual disorders, significant new de- 
velopments have emerged from VA laboratories in the fields of vision, 
audition and olfaction. 

Investigators at the VA Hospital, Sepulveda, Calif., studied the 
degeneration of photoreceptors and the neural connections of these 
visual cells in a recently discovered strain of mice which develop spon- 
taneous and profound retinal degeneration in the first few days of life. 
Comparison of the biochemical status of these peculiar retinae with 
that of normal retina suggests that the inherited abnormality involves 
certain classes of retinal nerve cells more than others. The relation- 
ship of this acquired blindness in the mouse and human disease is not 
clear but its study may define critical biochemical changes in retinal 
metabolism which occur in human disorder. 

At the VA Hospital, Martinez, Calif., investigators reported that, 
even in human subjects with normal hearing, a major asymmetry ex- 
ists in the perception of pitch when the two ears receive simultaneous 
tones of different frequency. Further analysis has indicated that the 
spectral and intensity information of an auditory stimulus are dis- 
sociated and processed by separate channels in the nervous system. 
At a later stage in the neural processing, the two types of information 
are recombined. By developing computer-controlled audiological test- 
ing procedures, both the dissociation and the subsequent recombina- 
tion of pitch and intensity information are being investigated in pa- 
tients with hearing disorders due to cochlear and central nervous 
system damage. 

The receptor cells of the olfactory organ — unlke those of the other 
special senses — are directly exposed to the atmosphere and are thus 
subject to infection (chronic rhinitis) as well as to damage by air-borne 
toxic material. Despite this exposure, most individuals retain their 
sense of smell throughout life. Other neural tissue has a limited ability 
to regenerate but investigators at the VA Hospital, Philadelphia, Pa., 
showed that olfactory receptors retain a significant capacity to regene- 
rate. Study of this model may assist in understanding the regeneration 
capacity of other neural cell types. 

Nuclear medicine and radiation 
Inst rumentation 

The impact of fundamental research upon clinical medicine was 
recognized during the past year when Dr. William H. Oldendorf, 



55 

Medical Investigator at the VA "Wads worth Hospital Center, Los 
Angeles, Calif., was awarded the first Ziedses Des Plantes Medal, 
named for the Dutch pioneer radiologist, by the Physical Medicine 
Society of Wurzburg, Germany. Dr. Oldendorf's original work in 
the field of neuroradiology, "Isolated Spot Detection of Radiodensity 
Discontinuities," was published in January 1961 in the IRE Transac- 
tions on Biomedical Electronics. It provided the basis for the develop- 
ment of computerized axial tomography, a technique which, when 
perfected by English medical investigators, revolutionized instru- 
mentation in X-ray diagnosis. A whole new category of instruments 
called the CATS (computerized axial tomographic scanners) has 
arisen from the fundamental investigation. CATS utilizes an X-ray 
source and a computer system to produce cross-sectional (tomo- 
graphic) X-ray images of the brain, allowing early and accurate 
diagnosis of central nervous system abnormalities. The new technique 
has now been extended to systems capable of imaging the entire body. 

This year, VA investigators at West Roxbury, Mass., developed a 
small cadmium telluride semiconductor probe and evaluated its use 
in the detection of acute infectious tooth abscesses in animals follow- 
ing the administration of an isotope radiopharmaceutical, Techne- 
tium-99m polyphosphate. The isotope uptake detectably increased 
in abscessed teeth within one to two weeks after infection ; intra-oral 
X-rays required four weeks for positive detection. The cadmium 
telluride probe distinguished contiguous normal and infected root tips 
less than 1 cm apart whereas the standard sodium iodide detectors 
were unable to distinguish normal root tips of an uninfected tooth 
between those of two adjacent infected teeth. 

The idea that computers can better define lesions which are demon- 
strated on Xuclear Medicine scanning equipment led VA investigators 
at Milwaukee. Wise, to develop and prove a method using a mini- 
computer to enhance lesions demonstrated in patients by scintillation 
camera images. The technique makes enhancement by fast fourier 
transform techniques available to all Xuclear Medicine laboratories 
that have mini-computers. A different approach by VA investigators 
at Gainesville, Fla., developed a computer program that eliminates 
gamma ray scattering within the patient and the penetration of the 
collimator septa. Correction for these and for nonuniformity of the 
instruments' crystal response significantly improved Technetium-99m 
brain scans in those regions with the most activity. Xon-radioactive 
lesions of the liver, not defined by raw images, were made manifest 
by computer-processing. The computer program provides greater 
validity of radionuclide distribution and assists in improving diag- 
nostic accuracy. 

An image intensifier camera was developed at the VA Hospital. 
Denver, Colo. This special high-sensitivity gamma-ray stationary 
imaging device is ideally suited for performing dynamic studies of 
the heart and great vessels. This is the first medical application of a 
unique light-sensing device linked to a digital computer for the diag- 
nostic use of gamma rays. 

Another approach to the use of computers in Xuclear Medicine Was 
provided by the VA group at St. Louis, Mo. Data obtained from 
patients by uniform, >:iundardized techniques using radioisotope? are 
entered directly into computers and transmitted by telephone to a 



56 

central site at the John Cochran Hospital in St. Louis where the 
results are interpreted. In this manner the VA hospitals at Jefferson 
Barracks. Mo.. Marion, 111., and Poplar Bluff, Mo., conduct and re- 
ceive the results of static and dynamic studies without having a 
Nuclear Medicine physician in residence. The technologist's use of 
the equipment at each hospital is simple and the telephone transmis- 
sion of images is accurate enough to provide efficient diagnostic 
services. 

Radiopharmacy 

Xew procedures in nuclear medicine often require the development 
and production of radiopharmaceuticals which concentrate in specific 
areas of the body, allowing diagnosis of specific abnormalities. The 
VA group at Los Angeles, Calif., reported the development of a 
technetium-penaciJlamine-Acetozolamide complex for renal scanning 
and has used the new agent to diagnose various kidney diseases. The 
substance localizes in the renal cortex and is cleared very slowly from 
the circulation producing excellent renal images. Technetium-tHhn- 
penacillamine. a pharmaceutical of great promise in visualization of 
the gall bladder, was investigated by the same group which also de- 
veloped 1-131- and Teclmetium-99m labeled metronidazoles as agents 
to reveal amebic hepatic abscesses. Studies throughout the world have 
demonstrated the latters efficacy in the diagnosis and localization of 
such abscesses. Indium 113m sulfide macroaggregate. an excellent lung 
scanning agent, was found to be easily prepared and useful where 
Technetium-99 compounds are not available. 

VA investigators at I lines. 111., described an improved generator 
devised as a prototype to provide continuous production of 81m Kryp- 
ton for clinical use. The Krypton may be delivered as a liquid or a gas, 
has a half -life of 13 seconds and emits gamma rays which are ideal 
for imaging. Krypton 81m allows the selective visualization of blood 
vessels, determination of the size, configuration and location of in- 
farcts as well as localization of vascular insufficiency and pathologic 
sites of absent, increased or decreased circulatory exchange. When 
infused at a constant rate into the artery leading to an organ or an 
anatomic region, the gas reaches equilibrium. In this steady state 
radioactivity remains constant within the blood vessels but the gas 
diffuses into the extra-capillary space and then changes more slowly 
than the gas in the vessels. Thus, still pictures can reflect the adequacy 
of capillary exchange. 

At the 'VA Hospital. Sepulveda. Calif., methods of producing 
aminoacids labeled with 13 nitrogen have been developed. Nitrogen 13 
has a half-life of 10 minutes, but it is used as a label to ma]) the body 
distribution of many compounds, Most compounds have been labeled 
by Blow and uncertain methods. The hivestigators developed an 
enzymatic synthesis which is rapid, produces no intermediates and 
yields a specific end-product. Sal 'is factory 13 nitrogen-L-alanine has 
synthesized by binding the two required enzymes on a solid 
supporl so thai the end-product contains none of the enzymes. Usually 
antibodies are conjugated with various non-radioactive compounds 
in order to locate antigen-antibody reactions at the cellular and intra- 
cellular level. 



57 

At the VA Center, Los Angeles, Calif., radionuclides such as 
Indium 111 were bound to antibody without destroying its ability to 
participate in immune reactions. Transferrin, d-penacillamine and 
desferoxamine were conjugated to antibodies by a coupling compound 
without losing their reactivity. 

At the VA Hospital, San Diego, Calif., a new non-stannous renal 
scanning agent, Technetium- 99m thiomalic acid, was developed. It 
compares favorably with available kidney scanning agents and avoids 
tin's interference with subsequent studies in which Teehnetium-99m 
pertechnetate is used as a diagnostic agent. 

At Ann Arbor, Michigan, investigators evaluated twenty-four se- 
lected testosterone analogs using prostatic tissue in order to discover 
a compound that would visualize and possibly treat prostatic carci- 
noma and its metastases. The results suggest that such a compound 
is feasible. 

Tumor diagnosis and treatment 

In order to study bone imaging for the early detection of skeletal 
metastases, research into the kinetics of polyphosphate and di- 
phosphonate labeled with Technetium-99m has been pursued at the 
VA Center. Los Angeles. Calif. VA groups at Los Angeles and St. 
Louis, Mo., have demonstrated that bone images with Technetium 
polyphosphate are sensitive indicators of bone lesions and are superior 
to X-ray examination or previously utilized radio-nuclides for the 
early detection of bone metastases. With low toxicity, ready avail- 
ability, economy, shortened procedure time, and a low radiation dose, 
new bone seeking compounds are now the agents of choice for search- 
ing for bone metastases. 

Studies have also demonstrated the utility of bone-scanning in the 
assessment of other disease entities. At the VA Hospital. San Diego, 
Calif., the use of the bone-scan as an early sign of degenerative 
arthritis was compared to physical evaluation, plane X-rays, and 
arthrograms in 60 patients undergoing evaluation for surgery. Surgi- 
cal arthroscopic examination.^ were obtained in 20 joints. In the less 
involved joints, the bone-scan was most sensitive to pathology, the 
arthrogram second and the plane X-rays third. Physical examination 
was least sensitive. At Los Angeles, VA investigators found pyrophos- 
phate kinetics and imaging to be very sensitive for the early detection 
of skeletal lesions in pseudo-hypoparathyroidism and the most sensi- 
tive diagnostic imaging procedure revealing bone lesions in primary 
hypoparathyroidism. 

At the VA Hospital. Tuscon. Ariz.. Gallium-67. a radio-pharma- 
ceutical which concentrates in soft tissue turners, was compared with 
111-Indium-labeled bleomycin, an anti-tumor antibiotic. Ninety per- 
cent of involved sites were correctly identified with Indium-labeled 
bleomycin but with no greater specificity than Gallium-67. More tumor 
types have been visualized with Indium-labeled bleomycin, especially 
gynecological and gastrointestinal tumors and it does not accumulate 
in the intestine. 

VA investigators at San Diego. Calif., evaluated a radionuclide 
staging protocol for bronchogenic carcinoma. The radionuclide search 
for metastases included liver, brain and bone scans using Technetium- 
99m labeled radiopharmaceuticals and Gallium-67 Citrate imaging. 



58 

Among the first 30 patients studied preoperatively ten went to sur- 
gery ; 100 percent of the tumors were resectable at thoracotomy. This 
contrasted with previous experience: only 60 percent of unsearched 
patients had resectable lesions. Gallium- 67 imaging of the chest con- 
firmed that nearly 100 percent of bronchogenic carcinomas take up 
the radionuclide. 

In a search for new radiopharmaceutical agents that are more useful 
in the characterization of tumors, another group of VA investigators 
at San Diego evaluated and developed radioiodinated tetracycline as 
a tumor scanning agent. In animals bearing an implanted hepatoma 
1-131 tetracycline compared favorably with Gallium-67 as a tumor- 
scanning agent and more frequently demonstrated tumors with some 
degree of necrosis. 

Investigators at the YA Hospital. Hampton, Va., evaluated treat- 
ment with 32-P of severe bone pain from diffuse metastic tumors, 
especially prostatic carcinomas. Radioactive phosphorus alone did not 
work; however, parathormone in conjunction with radioactive phos- 
phorus was very effective in relieving bone pain. 

Central nervous system 

The VA group at Brooklyn. X.Y.. has described the selectivity of 
phlorizin as an inhibitor of glucose transport. The presence of a 
phlorizin-reactive cell t}<pe in the ventro-medial hypothalamus sug- 
gests that special gluco-receptor cells in this area are involved in the 
regulation of food intake. VA investigators at San Diego, Calif., 
injected hyperbaric solutions of amphotericin and dextrose mixed with 
1-131 albumin into the lumbar space of monkeys. When placed in the 
Trendelenburg position (feet elevated), the animals had higher cis- 
ternal concentrations than monkeys given non-hyperbaric solutions 
and kept supine. This technique may prove useful in the treatment of 
fungal meningitis. 

At the VA Hospitals, Palo Alto, Calif., and Minneapolis, Minn., 
the use of radionuclides and the gamma camera in the visualization of 
blood flow was evaluated in patients with carotid-cavernous sinus 
fistulae. The technique is simpler, less traumatic and less hazardous 
than older methods. 

At St. Louis, Mo., VA investigators demonstrated decreasing 
peritumor concentration in brain scans performed with Technetium- 
99m pertechnetate following the administration of a cortico steroid 
for the treatment of cerebral edema. The apparent decrease in tumor 
size was due to a diminution in edema around the tumor. 

Cardiovascular studies 

Various aspects of cardiac function have been examined using a 
gamma camera and computer processing following the administra- 
tion of intravenous radionuclides. At the VA Hospital, Seattle, Wash., 
animal studies confirmed that the visualization of myocardial blood 
flow at rest and during stress provides new diagnostic information. 
In approximately 200 patients, the radionuclide method proved more 
sensitive than clinical history, EKG or coronary arteriography in 
detecting areas of scarred myocardium. The technique determined the 
effect of coronarj arterial constriction on blood flow to the working 
heart, and identified arteries which need surgical therapy. In addi- 



50 

tion, VA groups at Miami. Fla., and Hines. 111., have evaluated the 
concentration of a radiopharmaceutical, Technetium-99m-labeled 
phosphate, in acute myocardial infarctions. This procedure shows 
promise in the diagnosis of acute myocardial infarction. 

At San Diego, a non-traumatic and non-invasive radionuclide tech- 
nique was developed for determining cardiac function. It appears 
particularly useful for the serial evaluation of acutely ill patients and 
for followup of non-hospitalized patients. 

Investigators at the VA Hospital. Denver. Colo., have utilized 
non-invasive radionuclide techniques and computer processing in order 
to determine mitral and aortic valvular insufficiency. There was close 
agreement with conventional contrast angiographic studies with the 
advantage that the radionuclide procedure does not require cardiac 
catheterization. 

Miscellaneous 

At the VA Hospitals in St. Louis. Mo., and Pittsburgh. Pa., bone 
marrow scanning was used to evaluate most of the blood forming 
tissue of the body. Patients with various blood disorders could be 
partially classified according to the pattern of the bone marrow scan. 
Such scanning helps locate tumors or malignant diseases involving 
the bone marrow, liver or spleen as well as diseases such as sickle-cell 
anemia associated with increased bone marrow activity and the 
marrow expansion into bones that are not normally blood-forming 
organs. The techniques also determine bone marrow death and serial 
studies of patients with chronic myelocytic leukemia suggest that the 
bone marrow scan may be of prognostic significance. At St. Louis, 
studies on transplanted kidneys demonstrated that Technetium-99m 
sulfur colloid uptake by the transplanted kidney helps to differentiate 
acute tubular necrosis from transplant rejection. The diagnosis can 
be established prior to other diagnostic changes and allow prompt 
initiation of appropriate therapy. 

Nursing research 

Projects by nurse researchers provide evidence of their commit- 
ment to improve patient care through clinical nursing research. At 
Salt Lake City, Utah, a VA-Brigham Young University study indi- 
cated surprisingly low correlations between patient-care scores and 
performance scores. Education was related positively with patient 
care and nursing performance measures. A VA research study partly 
sustained the hypothesis that patients on medical-surgical units re- 
port less omissions in nursing care when the pattern of care is pri- 
mary nursing than when it is team nursing and that satisfaction with 
care was higher in the primary nursing group than in the team nurs- 
ing group of patients. 

Two studies dealt with the evaluation of structured means of nurs- 
ing assessment or data-gathering and provided information in a major 
area of concern: at the VA Hospital Center (Wadsworth), Los An- 
geles, Calif., investigators studied nursing assessment and care plan 
statements, and at the VA Hospital. Long Beach. Calif., others devel- 
oped a patient-completed admission questionnaire and compared it 
with the nursing interview. 



60 

For many years it has been recognized that good relationships be- 
tween physicians and nurses improve patient care and that the sep- 
aratism between medical and nursing education may produce physi- 
cians who are insensitive to the knowledge and skills of nurses and 
other health professionals. A study at the VA Hospital. Madison, 
AVis., evaluated one method of introducing nursing procedures to 
medical students. Most medical students felt that the experience was 
valuable and that the trials should be continued. 

Half of all VA Hospitals have a Xursing Research Committee, 
teach a course in research methodology for nursing staff, use a nurs- 
ing research consultant on a regular basis, and/or participate in re- 
search studies directed by large outside organizations such as Western 
Interstate Commission on Higher Education (WICHE), Southern 
Regional Board of Education (SREB) or Division of Xursing (NIH- 
HEW) . During the past year, VA nurse researchers participated and 
presented papers at 5 Nursing Research Conferences : at VA Hospitals 
in Shereveport, La.; San Antonio. Texas; Prescott, Ariz.; Murfrees- 
boro, Tenn. ; and at Central Office Xursing Service, Washington, D.C. 
In addition, doctoral nurse researchers and the Chief Nurses at their 
sites met at Palo Alto, Calif., to discuss research in the patient set- 
ting. These conferences were attended by large numbers of VA nurses 
and by university faculty members involved in joint VA-University 
investigations. Doctoral nurse researchers are located in fifteen VA 
settings. 

Oncology 

The VA has pioneered in clinical studies of therapy for neoplasms 
common in veterans and VA hospitals provide the largest, most uni- 
form group of patients with neoplasia available for trials of new thera- 
peutic agents or approaches to cancer. In order to carry out such 
studies, the Veterans Hospital Cooperative Research Groups with rep- 
resentatives from VA hospitals throughout the country develop uni- 
form protocols for the therapy of various types of neoplasms. 

Because large numbers of patients can be treated according to such 
protocols the VA Cooperative Groups can answer clinical questions 
promptly and efficiently. Such VA studies have provided definitive 
answers to important clinical questions regarding the optimal manage- 
ment of such common diseases as carcinoma of the prostate, of the 
lungs, and of the colon and rectum. 

The study of rectal cancer, for example, has demonstrated an in- 
creased five-year survival rate, to 47 percent, for patients undergoing 
surgery and treated with pre-operatrve x-ray therapy when compared 
to only 34 percent of those treated with surgery alone. The preopera- 
tive radiation therapy was able to lower the percentage of patients 
with carcinoma, metastatic to lymph nodes, from 45 percent to 27 
percent. 

Another VA Cooperative Study concerns the treatment of non-re- 
sectable cancer of the lung using only chemot herapy of various types 
when compared to combination treatment with radiation therapy and 
y. The results to date indicate that no combination of 
drugs or combined therapy is superior to treatment with cyclop 
phamide alone. 



61 

The VA Cooperative Urologic Research Group correlated the pre- 
treatment serum corticosteroid values with the survival of patients 
with prostatic cancer. The higher the initial value of serum non-pro- 
tein bound Cortisol and 17-hydroxy corticosteroid, the greater the 
probability of death during the first year of treatment, regardless of 
the treatment or stage of the disease. 

The increasing emphasis on basic research related to cancer has re- 
sulted in the establishment of a Merit Review Board in Oncology. The 
multidisciplinary nature of its membership has strengthened the 
ability of the Board to provide expert review of proposals and to sug- 
gest improvements in experimental design. 

VA Hospital, Salt Lake City, Utah, has reported new findings on 
the role of macrophages in resistance against cancer. Macrophages 
which are present in all tissues have generally been considered to be 
scavenger cells that remove foreign material and dead cells in order to 
maintain a constant internal environment. The VA investigators es- 
tablished an important role for macrophages in the recognition and 
destruction of tumor cells as well. Macrophages which have been acti- 
vated by immune stimulants such as bacilli Calmette Guerin (BCG) 
have the ability to recognize specifically and to destroy tumor cells 
while leaving normal cells unharmed. Macrophages destroy tumor cells 
by the transfer of lysozymes. which are subcellular structures contain- 
ing toxic chemicals, to tumor cells. These lysozymes of macrophage 
origin then cause the destruction of the tumor cells. Although these 
studies were conducted with experimental animal neoplasms, improved 
knowledge of the natural defenses against tumor growth in animals 
may lead to more rational treatment for human cancer and to an under- 
standing of the mechanism of action of immunotherapeutic agents 
already being used in man. such as BCG. 

At Minneapolis. Minnesota. VA researchers demonstrated that 
patients with bladder cancer have lymphocytes capable of killing 
bladder cancer cells in tissue culture. The investigators also found that 
some patients with transitional cell carcinoma of the urinary tract 
have sera which contain (IgG) antibodies and induce lymphocytes 
obtained from normal subjects to kill transitional cell carcinoma target 
cells specifically. These antibodies may prove useful in the immuno- 
therapy of bladder cancer. The same investigators found that the 
serum from some patients with carcinoma of the kidney contains anti- 
bodies which can act alone to kill tumor cells in tissue culture. 

At the VA Hospital, Oklahoma City. Oklahoma, investigators 
found factors in the serum of patients with leukemia which impair the 
function of the lymphocytes responsible for cellular immunity against 
cancer. They have observed that a significant decrease in the inhibi- 
tory activity of the serum from leukemic patients occurs during re- 
mission and reappears with relapse. 

At Denver, Colorado. VA investigators studied the role of immuno- 
suppression by drugs during organ transplantation on the develop- 
ment of malignancies in these patients. The immunosuppressed organ 
homograft recipients showed an increased incidence of malignancies 
to 5.6 percent incidence some time after transplantation. 

At Washington, D.C., the VA and the National Cancer Institute 
have developed a joint inter-agency unit, located at the VA Hospital. 



62 

This 30-bed unit has three functions: (1) to provide intensive workup 
and treatment of VA patients in consultation with the medical staff ; 
(2) to evaluate the role of new anticancer agents in the management 
of neoplasms commonly occurring in VA patients; and (3) the treat- 
ment of patients with lung cancer, the most commonly lethal cancer 
in the United States. Current studies concern the development of 
chemotherapy with new combinations of drugs for lung cancer and 
the natural history of lung cancer in man. 

At Milwaukee, Wisconsin, VA investigators observed that broncho- 
genic carcinoma with metastases to the liver induced the formation of 
alpha-feto protein in the surrounding normal liver cells. Since alpha- 
feto protein is thought to be found only in the serum of patients with 
primary liver cell cancer and embryonal carcinoma, the mechanism 
by which the bronchogenic carcinoma cells induces the normal liver 
to produce alpha-feto protein may be of considerable importance. 

At Sepulveda, California, a specialized unit for the care and study 
of cancer patients has been established and investigators have been 
involved in studies of cancer treatment by surgery and immunotherapy 
BCG, a live but attenuated bovine tuberculosis baccillus, is used as 
an immunotherapeutic agent against cancer. Since it is given as a 
living vaccine to cancer patients, many of whom have a depressed 
immune system, patients may occasionally develop a form of a typical 
tuberculosis caused by the living BCG organisms. The simultaneous 
administration of isoniazid. a drug effectve against tuberculosis can 
prevent this and VA investigators demonstrated that the drug does 
not interfere with the antitumor effectiveness of the BCG in animals. 
The same investigators found that BCG immunotherapy can be a two- 
edged sword causing either tumor regression or enhancement of tumor 
growth depending upon the method of its administration to animals 
with transplantable tumors. Conditions for achieving optimal im- 
munotherapy are important information for immunotherapy in man. 

Investigators at Sepulveda and UCLA, investigating immuno- 
therapy with BCG and other immune stimulants in the management 
of human neoplasmas, have found that BCG increases the immune 
response of tumor-associated antigens in melanoma patients. 

Investigators have found that many cancer patients' immune systems 
are defective as judged by their ability to develop immune reactions 
to common skin test antigens or to be sensitized to new antigens such 
as dinitrochlorobenzene. Patients who are immunologically unreactive 
to these antigens have a greater chance of developing recurrence fol- 
lowing cancer therapy than patients whose immune systems are normal. 
An important finding is that this immune nonresponsiveness does not 
exist before cancer develops but is a result of the cancer itself. For this 
reason, the immunosuppression can be reversed in some patients by 
removal of the cancer. 

VA invest Lgators have developed new tests to study the ability of a 
patient's leukocytes to respond to tumor antigens. The new techniques 
have demonstrated the presence of tumor-associated antigens in car- 
cinoma of the lung; an observation which may have significance for 
immunotherapy in lung cancer. In addition, serum antibodies in cancer 
patients are hound to tumor cells where they may play an important 
role in inhibiting tumor growth or in inhibiting the patient's lym* 
phocytes from causing tumor destruction in the patient s body. 



03 

The VA-NCI medical oncology branch 

Illustrative of VA capability in cooperative clinical studio?, and 
unique, successful, and long-term demonstration of inter-agency col- 
laboration is the VA-HEW program on evaluation of cancer therapies. 
Initiated in 1956 by an invitation from the National Cancer Institute 
to the VA Department of Medicine and Surgery, this program gave 
rise in 1957 to three separate multi-VA hospital collaborative study 
groups involving a total of 53 separate clinical services in VA hospitals 
focusing on cancers of the lung in several aspects, stomach, colon- 
rectum, and a series of hematogenous tumors as well as multiple 
myeloma and malignant melanomas. Two of these programs have con- 
tinued through the years. Others have been initiated or phased out. 
All have undergone periodic pruning for efficiency along with various 
evolutionary changes, reorganizations and reorientations in keeping 
with modernization of cancer therapies, promising leads in new di- 
rections, and some variations in available clinical material reflecting 
the frequency of various cancers in the population of VA beneficiaries. 

These programs provide both training grounds for medical students, 
residents and staff in VA hospitals as they come in contact with these 
efforts at improvement of cancer therapy, and a means for providing 
increased diagnostic and therapeutic attention to a far larger number 
of VA cancer patients than those actually included in the treatment 
programs. The latter is true since most VA patients entering partici- 
pating VA hospitals suffering malignancy, are carefully studied to 
determine whether they might in fact be included as study subjects. 
From this standpoint, the studies are a distinct enhancement of care 
for a ]arge number of VA patients suffering from cancer. 

As VA patients, subjects are fully supported by the VA Depart- 
ment of Medicine and Surgery in hospitalization, diagnostic studies 
and all aspects of their treatment and followup care. Therefore, costs 
to NCI for the VA cooperative clinical trials are kept to a minimum. 
Major allocations of NCI funds are for personnel and mechanisms of 
uniform study data collection, collation and analysis, and for meet- 
ings of investigators monitoring the program and discussing and re- 
porting study plans and results. 

At present, there are three cooperative studies under the interagency 
VA-NCI agreement, and a fourth, the VA Urology Cooperative 
Study Group, is funded through the NCI grants mechanism. All are 
described later in this report Tinder the section "Multi-Hospital Re- 
search — Cooperative Studies in Cancer." 

An additional collaborative program under the interagency agree- 
ment was initiated in 1968 at the VA Hospital, Washington, D.C., 
where joint VA-NCI staff are engaged in a series of integrated basic 
and clinical studies directly related to patient problems. 

The program with its overall approach to clinical cancer and more 
basic practical problems related thereto is considered by both VA and 
the NCI to be an economic and professional enhancement to the objec- 
tives and programs of both agencies. 

Oral biology 

The oral disease and dental research program in the VA is broadly 
based. Apart from the dental profession, 14= other biomedical disci- 



64 

plines are engaged directly and indirectly in investigations of oral 
disease and related dental health problems. 

Dental caries and periodontal diseases, the most endemic of man- 
kind's disorders, continue as major targets of the VA research pro- 
gram in oral biology. Dental caries has been shown to be multifac- 
torial, involving interactions between the human host, diet and micro- 
organisms. At the VA Hospital, Miami, Fla., investigators recently 
discovered that caries-producing oral bacteria selectively or preferen- 
tially metabolize and attack certain salivary proteins which differ 
from the salivary proteins metabolized by non-caries-producing bac- 
teria. This raises the question of whether an individual's saliva com- 
position is an important determinant of caries production. Also a prog- 
nostic test for dental caries may be developed on such criteria. Current 
studies are determining whether caries attack rates can be con-elated 
with salivary levels of the involved proteins. 

The Miami researchers are also pioneering the investigation of new 
antibiotic substances of a highly selective nature, called baeteriocins. 
These substances are highly toxic for certain bacteria but are pro- 
duced by closely related bacteria. The investigators are isolating and 
characterizing known baeteriocins and are seeking new ones made by 
non-caries producing organisms. This approach may also prove useful 
in the control of periodontal diseases. 

Saliva is involved in both dental caries and periodontal disease. At 
the YA Hospital, Houston. Texas, a unique influence of light upon 
salivary secretion was reported previously. It has been shown recently 
that darkness significantly decreases salivary secretion in the resting 
parotid gland while varied light sources were equally effective in 
maintaining higher flow rates. The importance of these phenomena in 
dental caries was shown first in studies; different rates of caries pro- 
duction were associated with exposure of experimental animals to 
different kinds of light sources. A collaborative study of the influence 
of light sources upon dental caries, by the VA Hospital, Hines, 111., 
and the Sarasota, Fla., County School Board, then showed that full 
spectrum light sources were associated with a lower incidence of caries 
in school children than were cool- white fluorescent sources. 

A Normative Aging Study at the VA Outpatient Clinic, Boston. 
Mass.. is designed to follow changes in human organ systems and func- 
tions as a result of the aging process. It includes saliva and salivary- 
gland research. Recent data from this study showed that levels of 
certain components of saliva including sodium, chloride, calcium. 
protein, amylase and PIT, decrease with age while the urea content of 
saliva increases with age. These changes reflect various aspects of 
glandular function. Thus, low sodium and chloride levels reflect less 
effective transport mechanisms of the glands while low calcium, pro- 
tein and amylase concentrations are related to decreased protein syn- 
thesis. The increase in urea levels may refleci diminishing kidney 
function as a result of the aging process since salivary urea levels cor- 
relate closely with blood levels of urea. 

Continuing studies of the intermediary metabolism of gingiva in 
health and disease at the VA Hospital. New York. X. Y., have demon- 
strated that mild and severe inflammatory states influence key oxida- 
tive enzymes of the gum tissue in different ways which appear related 



65 

to both degenerative and proliferative responses within the tissue. In 
addition, giugiyaj tissues were separated and fractionated into sepa- 
rate sub cellular components before the protein and enzyme distribu- 
tion within each component was characterized. The resulting data 
could then be related to such tissue processes as mitosis or cell divi- 
sion, protein synthesis and drug detoxification. 

The restoration of diseased tooth and oral structures constitutes the 
major and most costly aspect of dental care and the physical and 
chemical properties of restorative materials for such purposes are 
critical. At the VA Hospital, Sepulveda, Calif., the physical proper- 
ties of dental restorative materials as well as the principles of design 
of dental and oral restorations receive intensive study. Utilizing a 
comprehensive variety of test procedures including photoelastic stress 
analysis, fluorescence, histopathology. and standard mechanical prop- 
erty tests, a variety of plastics, adhesive materials and metal alloys 
are being screened. Recent work has concerned the possible develop- 
ment and use of non-precious metal alloys. 

At the VA Hospital, Ann Arbor, Mich., model systems are being- 
developed to permit establishment of a tooth bank, in which teeth 
would be stored for future re-implantation. Optimal temperatures, 
media and other parameters for tooth storage are emerging from this 
work which now uses experimental animals. Histopathologic and ra- 
dio-autographic techniques of analysis used to evaluate the re-implan- 
tations have indicated that it is feasible to establish tooth banks for 
humans. 

Pathology 

VA pathologists and laboratoiy scientists have investigated and re- 
ported on a wide variety of subjects concerned with the diagnoses or 
mechanisms of disease processes. Only a representative few studies 
will be described below. 

By means of electron miscroscopic studies, VA pathologists at New 
Orleans, La. were able to relate changes in cell structure to treatment 
and to the clinical status of a patient with Whipple's Disease. The 
cause of this uncommon but serious disorder, which occurs primarily 
in adult males, is still uncertain and the findings of this study sug- 
gest that the primary defect may be located within subcellular'struc- 
tures called lysosomes which play an important role in defending cells 
against infectious agents. 

At Bronx, N.Y.. VA researchers fouud that high doses of Vitamin 
C taken with meals may destroy significant amounts of another im- 
portant vitamin (B 12 ). The study emphasizes the possible hazards of 
the injudicious use of high doses of vitamin C as a home remedy 
against the common cold, particularly when taken with meals. 

VA pathologists from Albuquerque, X. Mex.. studying the effeds of 
x-rays on blood cells, reported differing degrees of sensitivity to radia- 
tion depending upon the origin and functions of such cells'. They de- 
tected differences by a relatively simply laboratory procedure. These 
studies have potentially important implications in" our understanding 
of immune mechanisms. 



66 

A VA pathologist at Hines, 111., studied the effects of the anti- 
tumor drug Vincristine on normal and leukemic blood cells and 
demonstrated that, in vitro, this drug can kill resting, as well as di- 
viding cells, but that leukemic lymphocytes were 10 times more sensi- 
tive to the drug than normal lymphocytes. These studies are important 
in understanding how some therapeutic agents exert their anti- 
leukemic effect. 

The development of atherosclerotic changes in vein grafts following 
sorto-coronary vein bypass surgery was reported by investigators at 
Wood VA Center, Milwaukee, Wise. Their observations have im- 
portant implications in evaluating the long term benefits of this in- 
creasingly common surgical procedure. 

At Palo Alto, Calif., VA researchers reported for the first time that 
malarial parasites can invade blood elements called platelets which 
play an important role in blood coagulation. This observation may ex- 
plain some of the complications of malaria. 

VA researchers at Denver, Col., devised a convenient small animal 
model for the study of brain changes and coma due to ammonia in- 
toxication. The changes occur very frequently in patients with severe 
liver disease due to alcoholism. The availability of the model provides 
a convenient means of evaluating different therapy and should lead to 
a better understanding of the mechanisms involved in this life- 
threatening condition. 

A VA pathologist at San Diego, Calif., devised a rapid and sensitive 
method for measuring serum haptoglobin, a protein compound which 
binds free hemoglobin in the blood stream. Haptoglobin assays are 
important in studies or reactions to blood transfusions, in diagnosing 
certain forms of anemias and in assisting to determine the cause of 
jaundice. 

A study of liver biopsies of drug addicts by pathologists at the VA 
Hospital, Houston, Texas, revealed a high incidence of tissue changes 
of a type usually associated with a foreign body reaction. These find- 
ings suggest that the filler substance usually present in street nar- 
cotics used intravenously are probably responsible for these tissue 
alterations. 

Rehabilitation medicine 

Rehabilitation Medicine Service (RMS) in the VA employs inter- 
disciplinary therapeutic teams to improve the physical and social 
function of veterans and to facilitate their adjustment to life in the 
community. Research in rehabilitation medicine concerns new methods 
of diagnosis and treatment in this area including joint research with 
meml)ers of allied disciplines, such as psychologists and orthopedic 
surgeons. 

Studies at the VA Hospital. Buffalo, N.Y., aimed at improving the 
irait of hemiplegic and other neurologically disabled patients. The 
flexion reflex which lifts the foot and leg in response to electrical 
stimulation of the sole was used in the gait retraining of hemiplegic 
patients. Electrical stimulation synchronized with the patient's at- 
tempt to walk, reinforced the weak flexor muscles of the partially 
paralyzed limb and assisted in the process of learning to walk. 



67 

Eventually, all the patients tested learned to walk without further 
assistance from this device but it permitted earlier gait training when 
the limb was still too weak to permit ambulation using conventional 
methods. 

The same group evaluated three forms of conventional below-knee 
bracing commonly used for hemiplegic patients. Using force trans- 
ducers, they demonstrated the hazard of knee instability with the 90° 
plantar-flexion stop brace as compared to two safer ones, the free- 
ankle and dorsi-flexion assist. 

A multi-disciplinary study involving the Biomechancis Laboratory 
of Case Western Reserve University, orthopedic surgeons and the 
Rehabilitation Medicine Service, VA Hospital, Cleveland, Ohio, was 
based on previous experience recording the force and loading measure- 
ments from microcircuitry instrumentation of a nail implanted in the 
thigh bone to treat a broken hip. The nail telemetered the forces im- 
posed on it by activities of daily living during the recover}' period. 

This technology has now been applied to prosthetic knee joints. 
Instrumented knee joints are being used to study the forces on this 
prosthesis during the critical post-operative period and as the patient 
resumes normal activities. 

The VA Hospital, Long Beach, Calif., is developing a clinical, 
teaching and research program focused on the common myofascial pain 
syndrome. Patients with shoulder girdle and low back pain usually 
have palpable bands in the involved muscles and the bands contain 
trigger points for referred pain but their nature has been contro- 
versial. An electromyographic study showed a transient contraction of 
the muscle in response to a specific palpation technique. This suggests 
that the palpable characteristics of the band depend, at least in part, 
upon the manner of palpation. 

An interdisciplinary study at the VA Hospital, Salem, Va., ex- 
amined results of an 84-day alcoholism treatment program. The regi- 
men is based on traditional socio-psychological treatment combined 
with a physical fitness program. Entry phychological testing and 
physical fitness testing used the average score of six functional 
measures and showed that depression is a cardinal characteristic of a 
person hospitalized for alcoholism. Patients gave test responses 
characteristic of immature anxious persons in poor physical condition. 
Following treatment, depression and blame projection decreased as 
physical fitness increased. This newly-validated testing technique is 
being used to determine which patients respond best to which kind of 
treatment. 

Research at the VA Hospital, St. Cloud, Minn., offers an example of 
an interdisciplinary approach. A local grade school and the hospital's 
rehabilitation staff conducted a remotivation program for elderly, 
mentally ill patients in close cooperation with the Psychology Service 
and the community. More than 200 sixth-grade children from social 
studies classes demonstrated the value of a regular, structured remo- 
tivation program held by the school children in the hospital. Objective 
measures showed significant improvement in patient attitudes and 
independent functioning. The elderly veterans thoroughly enjoyed and 
were stimulated by their youthful friends who were in turn delighted 
and reinforced by their appreciation responses. 

70-799—75 6 



68 

The Kinesiology Research Laboratory of the VA Center. Wood, 
Wis., with the Orthopedic Service measured objectively the physical 
characteristics of gait using sophisticated kinematic and electronic 
equipment. There was an initial rapid gain in gait pattern during the 
first six months after a McKee-Farrar total hip replacement and most 
patients continued to improve for 24 months. This correlated closely 
with subjective clinical impressions. Such a study could objectively 
compare the results of different artificial hip procedures and variations 
of them. The laboratory developed a simple and effective force plat- 
form to measure postural stability and steadiness. Normal, stable sub- 
jects permitted a wide variation in the area over which weight is safely 
shifted while the average center of pressure remains remarkably close 
to a central point. This system provides an accurate, objective method 
of measuring the degree of postural stability so essential to safe ambu- 
lation in hemiparetic veterans and veterans with other neurological 
disabilities. 

Respiration and pulmonary disease 

Humoral mediators of lung disease 

VA hospitals in Dallas, Tex.. Wood, Wis., and Tucson. Ariz., report 
progress in the identification and measurement of chemical agents 
that may medicate a variety of pathologic processes in the lung. These 
processes include the bronchoeonstrietion of asthma, the rise in pul- 
monary vascular pressure associated with reduced oxygenation of the 
tissues and with pulmonary embolism and the fall in systemic arterial 
pressure complicating serious lung infections, pulmonary embolism 
and lung injury. 

Cancer of the lung — by far the most common cancer in veterans — 
may be detectable at a relatively early stage by special blood tests. 
These tests depend on the radioimmunoassay of hormones, normally 
not detectable, but increased in patients with bronchogenic carcinoma. 
A report from the VA Hospital. Bronx, N.Y., discusses the measure- 
ment of ACTH. a hormone normally secreted by the pituitary gland, 
as a screening device for identifying patients with early lung cancer. 

VA medical investigators at Dallas. Tex., reported that a new hor- 
mone, vasoactive intestinal polypeptide (VIP), is elevated in observed 
cases of watery-diarrhea syndrome, and several oncogenic tumors, 
indicating that excess VTP appears to be a cause of chronic watery- 
diarrhea and may be derived from any of several different tumors. 
They also reported elevations in plasma VIP levels in some patients 
with lung cancer. VTP is an intestinal hormone: however, another 
related peptide is produced in the lung. It is probably this peptide 
thai is being measured by the assay. Current trials will determine 
whether the test is satisfactory for screening patients. 

Investigators at the VA Hospital, Seattle. Wash., reported that 
natural human fibrinopeptides have no effect on respiration and circu- 
lation in animals. 

Infectious diseases 

Severe lobar pneumococcal pneumonia is often associated with 

rice of bacteria (pneumococci) in the blood stream and carries 

a relai ively high mortality, especially in older patients. The possibility 



69 

of preventing a large number of these serious pneumonias by a 
program of vaccination has been investigated at the VA Hospital, 
Nashville, Tenn. 

They found that 60 percent of 43 patients with bacteremic pneu- 
monia and 55 percent of patients who died from their infections would 
theoretically have benefited from an immunization program designed 
to include all persons 50 years of age and older, and all younger 
patients with recognized underlying disease. 

More precise identification of bacteria responsible for causing lung 
abscess and other acute bacterial infections of the lung should lead to 
more effective treatment by selecting the most appropriate drugs. This 
research is being carried out at the VA Hospital. Sepulveda, Calif. 

A study of bacteria isolated from primary lung abscesses followed 
by antimicrobial therapy selected according to the type of bacteria 
present in the abscess, was judged successful in all cases by investiga- 
tors at the VA Hospital Center, Los Angeles (Wads worth ) % Calif. 
Another study at this same hospital, found that anaerobes ("un- 
doubtedly the most overlooked bacterial pathogens of the lower res- 
piratory tract") were the predominant cause of aspiration pneumonia 
and a major cause of empyema. 

Tuberculosis of the lung remains a health problem, even in the 
United States where 30,000 known new cases appear annually and 
hundreds of thousands of persons have relatively controlled disease. 
VA research in this area has included studies at Long Beach, Calif, 
and Madison. Wis., of the metabolism of the causative organism. 

Long Beach investigators found that 3-amino 1,2,4-triazole stimu- 
lates the catalase produced by Mycobacterium tuberculosis in contrast 
to its inhibitory effect on catalase from other sources. Another study 
at this same hospital, of vaccination with BCG (bacillus Calmette- 
Guerin) found that there was no significant difference in the tuber- 
culosis bacilli recovered from animals' spleens or lungs, regardless of 
the age of the culture, the cultural conditions, or the immune status 
of the host. Madison VA investigators found that by exposing Myco- 
bacterium tuberculosis to isoniazid. it inhibited cellular mycolate syn- 
thetase activity and that the activity was reactivated after a time-lapse 
in exposures of up to 10 hours. The inhibition became irreversible in 
exposures of more than 10 hours. Rifampin in twice as potent a dose 
was shown to limit protein in M. tuberculosis but only moderately 
inhibited cellular mycolate synthetase activity. Hence, the restoration 
phenomenon is thought not to involve protein synthesis. 

An interesting discovery of infectious particles called "xenosomes" 
was reported from the VA Hospital. Miami, Fla. These self -replicat- 
ing protozoa, smaller than bacteria but larger than viruses, may pro- 
vide a better understanding of DXA replication which is important in 
all cell functions, and of the nature of the infectious process. 

D'aanostic techniques 

Research at VA Hospitals in Indianapolis. Ind. and Denver, Colo., 
has confirmed that it is possible to obtain lung tissue for histologic 
or pathologic examination through the flexible bronchoscope. The 
method is simple and relatively free from serious hazard. 
m Other techniques of diagnostic value have been under investiga- 
tion in a number of VA hospitals. VA investigators at Oteen, N.C., 



70 

reported on the dangers of needle biopsy of the lung, naming several 
"cutting type" needles which they condemned because of the number 
of severe hemorrhages reported after their use. 

At the VA Hospital, Gainesville, Fla., investigators reported a 
simple, practical method of estimating the function of human lungs 
after surgery. Experience in 13 cases shows that a number of vital 
post-pneumonectomy functions can be predicted. 

In Denver, Colo., VA investigators compared radiocardiography 
with dye dilution as techniques in animal studies. They found that 
isotopic radiocardiography yields an accurate and reproducible meas- 
urement of the time it takes blood to circulate through the lungs, and 
the volume of blood circulating in the lungs. 

Pulmonary arterial volume (PAV) was measured at the VA Hos- 
pital, Xew York, N.Y., by injecting the radioisotope 131 1-labeled mac- 
roaggregated albumin into the pulmonary arteries of an animal and 
tracing it through the lungs. It compared with Technetium-99m, 
another isotope commonly used, with little or no advantage for either. 

Pulmonary embolism 

Although pulmonary embolism (PE) already is responsible for 
50.000 deaths each year, the annual incidence in the U.S. continues to 
rise, mostly because of larger numbers of elderly people, more exten- 
sive surgery, and increased diagnostic sophistication, according to VA 
investigators at the VA Hopsital, Martinez, Calif. Nevertheless, pre- 
mortem diagnosis of pulmonary embolism is made in only 10 percent 
of the cases of those who die as a result of it. Investigations show that 
medical disorders are the most common cause of PE. Congestive heart 
failure or atrial fibrillation increase the incidence ten-fold. Deep 
venous thrombosis, pulmonary disease, and cancer, particularly car- 
cinoma of the prostate, ar high risks. Most important in management 
of PE, they report, is prevention of venous thrombosis. Recently pre- 
operative anticoagulation has been advocated to prevent postopera- 
tive emboli. 

A VA investigator at West Roxbury. Mass. reports an estimate of 
570,000 patients suffering non-fatal PE in the U.S. annually and 140,- 
000 PE fatalities. Plain chest X-ray is not universally appreciated, but 
a recent study shows a high diaphragm on the side where the embolism 
is located. Perfusion lung-scanning should be performed immediately. 
The literature gives ample evidence of underdiagnosis. The possibility 
of PE should be suspected more often then it is, the investigator sug- 
gests, and multiple-view lung-scanning should be performed in all 
patients suspected of possible PE. Unless angiography is performed, 
he states, evaluation for PE without lung-scanning should be consid- 
ered incomplete. 

Bronchodilators 

Investigators at the VA Hospital, Memphis, Tenn. demonstrated 
with animal models that adrenaline, a beta adrenergic agent, produced 
;i rapid increase in cyclic AMP. Isoprenaline was more stimulatory 
than adrenaline, noradrenaline was less stimulatory, and ephedrine 
produces a negligible effect. Caffeine and theophylline, methylxan- 
thines, produced an increase in cyclic AMP concentration. Of these, 
caffeine was the tnosi potent. It is likely that many of the beneficial 



71 

effects of these drugs in pulmonary patients occur through similar 
changes and modulations of the cyclic AMP system. 

Investigators at the VA Hopsital, Albuquerque, New Mex. devel- 
oped a high-pressure liquid chromatographic system to determine the 
presence of theophylline and its metabolites in human urine. 

The recently isolated vasoactive intestinal peptide (VIP), as men- 
tioned previously, has a wide range of biological actions, including 
vasodilation, hypotension, relaxation of isolated trachea and other 
smooth muscle organs, and stimulation of cyclic AMP production. VA 
investigators at Dallas, Texas demonstrated that in animal models 
the administration of VIP by aerosol affords good protection against 
bronchial and alveolar-duct constriction due to histamine or other 
factors. Protection by VIP was maximal after 1 hour and partial pro- 
tection lasted at least 3 hours. VIP caused no change in heart rate or 
blood pressure. 

Pathophysiology of lung disease 

Investigators at the VA Hospital, Indianapolis, Ind. studied oxygen 
transport during acute alkalosis and abnormally high concentration 
of inorganic phosphates in the blood. They found that hyperventilated 
animals, whether infused with inorganic phosphates or not, had de- 
creases in cardiac output and increases in the volume of oxygen in their 
lung tissue. 

At Wood, Wise, VA investigators made an electron microscope 
study of lung tissue of a patient with extensive fibrosis in both lungs 
They identified particles of cobalt, iron, chromium and nickel, and 
implicated cobalt as a possible cause of interstitial pneumonitis-fibro 
sis in industrial workers. 

At the VA Hospital, Little Rock, Ark., investigators studied en- 
largement of the heart in patients with chronic bronchitis and emphy- 
sema. Among 72 patients, they found 20 (78 percent) had enlarged 
left ventricles and that half of these had high blood pressure or arteri- 
osclerotic heart disease, or both. 

In a study of electrocardiographic diagnosis of enlargement of the 
right ventricle of the heart, which pumps blood to the lungs, in 
chronic obstructive pulmonary disease, investigators at the same VA 
hospital found that of 71 patients, 30 had definite, and 3 had probable 
enlargement of the right ventricle, and 18 patients had enlargement 
of the left ventricle. They found four criteria most reliable for analy- 
sis of ventricular enlargement and report that these critieria may be 
used effectively in predicting enlargement of the right ventricle of 
the heart in chronic obstructive pulmonary disease. 

In a study of allografted lungs in matched animals with induced 
pulmonary hypertension, medical investigators at the Oklahoma City, 
Okla. VA Hospital found that pathological symptoms developed simi- 
lar to the phenomena of chronically rejected renal allografts. 

Although constituents of marijuana have been identified and the 
physiological effects of tetrahydrocannabinol have been demonstrated 
(marijuana frequently contains cannabinol), VA investigators at In- 
dianapolis, Ind. studied its effects on animals. They found that animals 
treated with cannabinol showed a trend toward increase heart rate 
and decreased cardiac output. 



70-799—76- 



72 

Social sciences 

Social science research in the VA is clinical and intended to improve 
patient care. Some studies deal with the social functioning of VA 
patients in the hospital or community and with the evaluation of 
programs designed to enhance adjustment. Others concern psycho- 
social factors and their relationship to illness. 

Determining readiness for the discharge of psychiatric patients is 
difficult. At the VA Hospital, Waco, Texas, the Social Adequacy 
Eating Scale (SARS) is being developed to quantify eight areas of 
social adjustment. The brief scale was used to evaluate all psychiatric 
patients who were hospitalized more than six months and correlated 
significantly with a longer scale, which measured discharge readiness. 
The SAES was recommended as a means for detecting patients for 
return to the community. 

Once patients are identified as ready for discharge, the type of 
aftercare must be selected. Five studies have dealt with evaluating 
outplacement facilities and the quality of care. The effect of age on 
the outcome of foster care placement was examined with 57:2 male 
psychiatric patients due to be discharged from 5 VA hospitals. The 
men were assigned randomly to foster care preparation and placement 
or to continued hospitalization and were studied for one year. About 
73 percent of both older and younger patients were actually placed 
in foster care and they functioned and adjusted better than those who 
remained in the hospital. Only 14 percent were over age 60. Older 
patients responded slightly better to preparation than younger ones 
and older patients adjusted as well as younger ones in the community, 
with about the same return rate to the hospital. Foster care seems 
appropriate and probably underutilized by psychiatric hospitals for 
their elderly patients. 

In Miami, Fla., 1000 patients in community nursing homes were 
studied at the time of placement when the levels of disability, impair- 
ment, prognoses, and demographic variables were determined. Nursing 
homes were measured on a 71 -item scale providing scores for meals, 
services, policies, plant, records, and safety. Data were also collected 
on staffing hours, costs, and turnover rates. Patients were re-evaluated 
at six months and classified as living or dead; improved, unchanged 
or deteriorated; and discharged, still in the home, or readmitted to the 
hospital. The only variable consistently related to outcome was the 
number of professional nursing hours, a finding compatible with other 
studies where structural variables seldom predict the quality of care. 
Apparently the only way to improve the outcome is to increase the 
professional nursing hours. 

In the same Miami VA study ratings of 6 social workers with knowl- 
edge of the nursing homes agreed closely when they ranked 40 facil- 
ities on a 5-point scale ranging from high to low quality. To determine 
the relationship of their opinion to more standardized assessments, 
researchers without prior knowledge of the homes rated them on a 90- 
item scale. The two sources of data correlated well, suggesting that 
expert opinion could substitute for more costly first-hand assessments 
by visits. 

To alleviate critical housing needs of the elderly, consideration has 
been given to the use of vacated college dormitories but little research 



73 

has been done on the few intergenerational living complexes which 
exist. At the YA Hospital, Bath, N. Y., a sociologist reviewed attempts 
to use dormitories as housing for the elderly and warned that there 
are problems of isolation and undesirable architectural features. 

A controlled study of a volunteer program called Project Anchor 
was conducted in three YA hospitals. Volunteers helped recently re- 
leased mental patients to become reintegrated into the community. 
Eighty-nine patients were randomly assigned to 78 volunteers, and 82 
patients to an unaided control group. Data from interviews, ques- 
tionnaires and records showed little therapeutic effect of the volun- 
teers. The results question the uncritical use or funds and personnel 
for outpatient volunteer programs. 

YA staff are particularly concerned about social disability resulting 
from alcohol and drug abuse. In a suburban area of Los Angeles, 
Calif., a YA social worker collaborated with the medical school in a 
study of 74 high school students. Students' drug use, attitudes and 
behavior were measured. About half had used drugs in the previous 
year but none heavily. The youths resembled heavy drug users attend- 
ing free clinics except in their attitudes and life style. The heavy 
users were more like sterotypes of "hang-loose hippies." 

Also, at the YA Hospital, Houston, Texas, patients in two 60-day 
treatment programs for alcoholism were studied up to one year after 
discharge. The more traditional treatment such as psychotherapy 
produced less favorable results than the experimental ward-oriented 
treatment and patients receiving psychotherapy were slightly more 
disturbed. 

At the YA Hospital, Topeka, Kans., a clinical program for treating 
chemically dependent veterans involves five hours a week of alpha- 
theta training over a five- week period with ancillary programs of 
meditative and reverie states used as a problem-solving device. Psy- 
chological testing before and after treatment of 60 patients compared 
with controls showed significant trends toward a less depressive effect, 
improved impulse control, increased sensitivity to ones' own needs and 
feelings, and greater ability to handle aggressive feelings. 

In Miami, preliminary work on a project jointly funded by the Na- 
tional Institute of Drug Abuse and YA showed that 30 percent of 
patients left treatment in alcohol units and 25 percent in drug units. 
Dropouts tended to be older, fewer were married, and they had used 
drugs longer than those who continued treatment. Admission data on 
mood, attitudes, social functioning, and perception of the ward showed 
no difference between completers and dropouts. The initial levels of 
motivation and staff opinion about the need for hospitalization 
significantly identified dropouts. 

YA concern with social issues, such as increased violence, is demon- 
strated by two studies. From the YA Hospital, Cincinnati, Ohio, 148 
mental health workers were surveyed to determine how many patients 
seen in the previous year posed physical threats to others or to the 
therapist and how many had actually assaulted the therapist. Of 
6,720 patients, 9 percent presented assaultive threats to others, 2 per- 
cent to the therapist, and less than 1 percent actually assaulted the 
therapist. The rate was unrelated to the status of therapist as resident, 
student, or staff member. Eight general approaches to coping with 



74 

assaultive behavior were identified, all reducible to biological, psy- 
chological, and social influence. 

At the VA Hospital, Perry Point. Md.. domestic relations offenders 
in the state of Maryland were found to be significantly older, more 
passive in using services, less violent in criminal offenses, possessed of 
more military service and more dishonorable discharges, and more 
likely to be working at the time of incarceration than were other 
prisoners. Both correction and public welfare agencies appeared un- 
successful in coping with these domestic offenders. 

Two projects exemplify VA research which relates to family health. 
Life events, emotional trauma, and social problems have been cited as 
influencing the outcome of pregnancy. Investigators at the VA Hos- 
pital, Seattle, Wash., in conjunction with the university hospital, com- 
pared 23 post-partum mothers who delivered prematurely with 23 
full-term mothers of matching background. A Schedule of Recent 
Experience which estimates how much a person's life has changed 
during a limited period was used to assess events during the preg- 
nancy. Although the two groups reported about as much change, a 
clustering of such changes seemed to increase medical difficulties 
during pregnancy, and over 50 percent of the medical difficulties 
influenced the early onset of labor. 

The children of patients were added to part of the treatment pro- 
gram by the Renal Staff at the VA Hospital, Lexington, Ky. They 
had previously added wives of renal dialysis patients. Evaluation of 
the program led the staff to recommend working with the children 
of dialysis patients as a part of improving the total family functioning. 

VA's mission includes the education of health professionals. In a^ 
attempt to determine what criteria should select entrants to social 
work education. 58 entering graduate students were tested on attitudes 
concerning dogmatism, authoritarianism, and alienation, as well as IQ, 
and data were recorded on grade point averages and undergraduate 
majors. At the end of the academic year, the faculty on the one hand 
and field instructors on the other rated overall performance of the 
students. Attitudinal scales predicted faculty but not field instructors' 
ratings suggesting that field instructors should be more involved in 
selecting students and that schools should seek new screening devices. 

Spinal cord disorders 

The widening interest in spinal cord injury research covers all 
aspects of care. Research efforts have emphasized basic scientific 
aspects of early and continuing care of spinal cord injuries as well as 
determining the community's needs for treatment facilities. 

Spasticity has been and remains a major problem in the rehabilita- 
tion of spinal cord injury patients and many studies have been de- 
voted to denning the effects of the antispastic agent, Lioresal. Data 
obtained in the isolated frog spinal cord suggest that Lioresal acts 
essentially presynapltkally, possibly by beginning impulse conduction 
in pre-terminal axons. This mechanism might contribute to its clinical 
effects in spastic patients. Clinically, another drug. Dantrolene, im- 
proves functional abilities in spastic patients without contractures 
and eliminates painful spasms of the limbs and bladder. 



75 

Educational, vocational and psycho-social problems are of major 
importance in the rehabilitation of spinal cord patients. One study. 
at the VA Hospital. Memphis, Tenm, has established the role of the 
educational, vocational coordinator in the spinal cord injury service. 
Two other studies from the VA Hospital, Wood, Wise, have em- 
phasized the thrust of the psycho-ecological approach to environ- 
mental factors affecting spinal cord rehabilitation patients. Both 
studies showed that the psychologist plays an important role in the 
total rehabilitation of a spinal cord patient. 

Spinal cord injury research at the VA Hospital, Madison. Wise, 
has involved functional restoration following transection of spinal 
cord in mammals using grafts of autogenous brain tissue, sciatic 
nerve and nodose ganglion. Structural continuity was achieved in 
the animals grafted with autogenous sciatic nerve. At the VA Hos- 
pital, Palo Alto, Calif., the neuroglial response following experi- 
mental spinal cord transection was examined. In five fish, complete 
transection was followed by axonal regeneration, while in two fish, 
stumps failed to reunite. Xo fibrous gliosis was present in the descend- 
ing tracts. 

At the VA Hospital. West Roxbury. Mass., urodynamics have been 
extensively studied. The vascular component to intraurethral pres- 
sure was found to be small and changes in intraurethral pressure with 
sympathetic stimulation are mediated through changes in the smooth 
muscle of the urethra. Bladder filling is accompanied by increased 
sympathetic activity in the "internal sphincter." Methods of bladder 
rehabilitation during and after spinal shock were investigated and the 
technique utilized for monitoring urethrovesical pressures described. 
It was objectively shown, for the first time, that the external urethral 
sphincter displays a high resistance during spinal shock. 

Impotence is an important problem in patients with spinal cord 
injury. The VA Hospital. Miami. Fla. reported impotence as a compli- 
cation of external sphincterotomy — a possible complication well- 
known in this field. The same group reported their experience with 
the use of a penile prosthesis for the management of impotence. 

Urinary incontinence is of major importance, not only in neuro- 
genic bladder but also in post-prostatectomy patients. The treatment 
of this condition with electrical stimulation of the pelvic floor was 
investigated at the VA Hospital, Martinez. Calif. Pelvic floor stim- 
ulation succeeded in patients with stress and with congenital, iatro- 
genic, and postoperative urinary incontinence. 

The VA Hospital, New York, X.Y. reported a ten-year experience 
with colonic urinary diversion in patients with and without neuro- 
genic bladders. Among the advantages of this type of operation are 
minimal stomal stenosis, little residuum, less electrolyte disturbance 
and availability for high and low diversion. 

The VA Center. Wilmington. Del. reported promising experimental 
results^ in urinary stone disintegration utilizing electrohydraulic 
lithotripsy, a method which has been extensively utilized in Eastern 
countries. 

At the VA Hospital, Seattle, Wash., medical, social and psycho- 
logical evaluations were made of the value of ileal conduit diver-ion 



76 

in patients with defective development of the spinal cord 
( myelodysplasia) . 

Investigators at the VA Hospital, Portland. Oreg. involved the well- 
known abnormally high potassium content of the blood (hyperkalemia) 
following succinyl choline utilization in spinal cord injury patients 
during anesthesia. This complication can be prevented by using non- 
depolarizing muscle relaxants for patients with denervated skeletal 
muscle. 

In the area of neurosurgery, the VA Hospital, Los Angeles, Calif., 
reported the development of pseudomeningocele as a cause of progres- 
sive myelopathy one of the complications following certain types of 
spinal surgery. Other causes of neurologic deficit were found to be 
diverticula of the arachnoid, reported from the VA Hospital. Boston, 
Mass. and spontaneous spinal epidural hemorrhage as an unusual com- 
plication of chronic alcoholism, reported from the VA Hospital. San 
Diego. Calif. A group in the VA Hospital. Madison, Wise, showed that 
a true synovial cyst of the spine can cause pain in the neck. 

Investigators at the VA Hospital, Miami, Fla. described improved 
materials and methods for making transcutaneous stimulation in the 
treatment of pain. In the VA Hospital. West Iloxbury, Mass.. a group 
study reported for the first time in the United States the results of air 
myelogram in spinal cord injured patients. This examination may be 
one of the best for visualizing the entire circumference of the spinal 
cord pointing to the need for an operation. 

Problems relating to reconstructing and improving hand function 
in patients with cervical cord injuries are of great importance. At 
the VA Hospital, Cleveland. Ohio, careful selection of patients under- 
going tendon transfers improved grasping abilities. 

In another field, plastic surgery is of great importance and it was 
shown experimentally in the VA Hospital, New Orleans. La., that it 
is possible to increase flap survival by means of arterial venous anas- 
tomosis. In the same area of skin pathology, investigators at the VA 
Hospital, Palo Alto, Calif., have been studying wheelchair cushions 
to try to reduce pressure in the sitting position. 

Surgery 

Surgical research in the VA includes: (1) basic science in which 
surgeons have conducted research in organ and tissue preservation, 
immunology of transplantation, neurophysiology, cardiopulmonary 
physiology and collagen synthesis; (2) clinical research with con- 
trolled clinical studies of a new physiologic approach and/or new 
pharmacological adjuncts to existing surgical procedures including 
cooperative evaluations of immunological adjuncts to cancer surgery, 
coronary artery bypass surgery, or evaluation of new selective 
vagotomy procedures, for ulcer disease: (3) the development of r\ew 
'mechanical devices or operative procedures such as nuclear powered 
cardiac pacemakers, heart lung machines, artificial lungs or- new shunt- 
ing operations for intractable ascites in collaboration with engineers, 
physicists and chemists. 

During the past year in basic science research, significant progress 
has been made in the biology of wound-healing, especially of trouble- 



77 

some tissues such as cartilage. VA investigators at Palo Alto, Cali- 
fornia and Syracuse, New York demonstrated that electric currents 
and ionic fields exert a previously unknown but profound effect in the 
healing of bone and cartilage. New approaches to collagen synthesis 
were investigated at VA Hospitals in Tucson, Arizona, and Little 
Rock, Arkansas. 

The pathophysiologic events affecting cells, blood elements, and 
organ respiration were studied to provide basic information for the 
use of an artificial lung by investigators at the VA Hospital, Bronx, 
New York. VA investigators at Palo Alto, California are conducting 
a critical evaluation of myocardial function after ischemic insult. This 
has added greatly to the practical application of a quiet heart during 
delicate cardiac surgery. Organ systems are being improved with new 
knowledge accrued at the molecular and cellular level at Salt Lake 
City, Utah and Miami, Florida. The use of new oxygen-carrying 
fluids in the absence of blood has been demonstrated as well as the 
role of such agents as allopurinol and lysosome stabilizers to prevent 
cellular deterioration of organs on perfusion and storage for 
transplantation. 

In transplant immunology, the VA Hospital, Minneapolis, Min- 
nesota has made significant progress in the manipulation of lympho- 
cyte function, enhancement of organ grafting such as kidneys and 
skin and the alteration of tissue immunogenicity. Results of clinical 
renal transplantation here as well as at Richmond, Virginia have been 
significantly improved over previous years because of these studies 
together with the use of newly developed antilymphoblast and anti- 
thymocyte globulins. The VA Hospital, Denver, Colorado, continues 
to collect information on the long-term results of kidney transplanta- 
tion. One of the original transplant centers, the hospital now has many 
patients with ten-year survival and functioning grafts and other data 
on clinical and experimental liver transplantation. The results are 
constantly improving in this latter complex procedure. Also at Denver, 
investigators have defined a relationship between cancer and immuno- 
suppression in transplant patients and have established a transplant 
tumor registry. 

The biosynthesis of clot formation, and the prevention of throm- 
boembolism is being investigated at the VA Hospital in Albany, New 
York. Results of this study suggest that depressed ability to dissolve 
fibrin, basic to the formation of blood clots and deposits that narrow 
the channels of circulating blood, and accompanying biochemical 
changes may predispose patients to become atherosclerotic. In Bos- 
ton, this has already led to the use of new filter and extraction tech- 
niques for pulmonary emboli by non-operative methods. Medical in- 
vestigators studying animals were able to introduce through a jugular 
catheter, silastic ballons, dacron covered springs, and umbrella filters 
to strain out emboli that would otherwise be trapped in the lungs. 
They found the perforated umbrella filter to be most effective in pre- 
venting pulmonary embolism. 

Surgical bacteriology is being more fully delineated in host-patho- 
gen and pathogen-pathogen inter-relationships at seA^eral VA Hospi- 
tals. At Madison, Wis., a self -administered dip-strip device is re- 
ported to be used satisfactorily by the patients themselves to screen 



78 

for urinary tract infection — and the bacteria that cause it — in female 
subjects. At Miami, Fla., the varying sensitivity of micro-organisms 
to anti-bacterial agents (drugs) was studied in pure vs. mixed cultures. 
They found that organisms growing in mixed cultures showed de- 
creased sensitivity to the drugs in 30 percent of cultures and total 
obliteration of sensitivity occurring 10 percent of the time. They sug- 
gest that both pure and mixed culture sensitivity be done for all mixed 
infections, since this more clearly represents the clinical picture. At 
Hines, 111., a special relationship of gastric procedures to the develop- 
ment of new pathogenic bacterial flora has been shown. 

In clinical studies* the treatment of cancer using new immune ad- 
juvants such as Bacillus Calmette Guerin (BCG) is being evaluated 
at several VA centers including St. Louis, Mo., where investigators 
reported that uveitis and vitiligo were associated with BCG treat- 
ment of two patients for malignant melanoma. Both patients are living 
and well after 33 and 32 months of nonspecific immunotherapy. To 
explain this unusual response to treatment, they suggest BCG (and 
possibly isoniazid) may be able to foster a cytotoxic auto-immune re- 
action — in which the patient's own immune system attacks his own mel- 
anin-producing cells (pigment producing) in certain patients with 
melanoma. 

VA investigators at Los Angeles, Calif, began with the knowledge 
that, despite surgery, about four of five patients with malignant mel- 
anoma metastasis, or spread to lymph nodes, succumb to this metas- 
tasis of their cancer. They found that treating these patients with 
BCG as well as surgery reduced the incidence of metastasis after two 
years to half that of those treated by surgery alone; even when 
metastasis occurred in BCG patients it was delayed six months. Ninety 
percent of BCG patients with microscopic metastasis in one node, 
remained free of the disease compared to 40 percent of those who 
had larger tumors in multiple nodes. They suggest BCG has an in- 
hibiting effect on "micrometastases" of malignant melanoma. The 
study of gastric function at new molecular and subcellular levels as 
well as in the controlled clinical multi-institutional evaluation of op- 
erative procedures such as selective vagotomy, vagotomy and pyloro- 
plasty and antrectomy is yielding definitive answers to the old surgical 
questions of dumping syndrome vs. recurrence rates and as to which 
patients should have which operations. A VA study at Houston, Texas 
was a prospective evaluation of vagotomy-pyloroplasty vs. vagotomy- 
antrectomy surgical procedures for treatment of duodenal ulcers. With 
a 5- to 8-year followup on 200 operations, the Chief Surgeon at the 
Houston VA Hospital concludes that vagotomy-antrectomy is the su- 
perior procedure for most patients because it is associated with fewer 
recurrent ulcers without a significant difference in the severity of 
other postoperative gastrointestinal complaints. 

The, closer metabolic study of obesity and objective clinical trials 
of jejuno-ileal bypass surgery is beginning: at VA Hospitals in Los 
Angeles, Calif., 'Syracuse. N.Y., and Baltimore, Md. 

New approaches to anesthesia using scientifically validated modi- 
fications of acupuncture and electroanesthesia are being initiated at 
the VA Hospital in Gainesville, Fla. Here investigators performed 
1)7!) acupuncture treatments in 201 patients with chronic pain. A sub- 
stantial number of the patients stated that they had relief immedi- 



79 

ately following a series of four acupuncture treatments. It did not 
matter whether the needles, were placed in the traditional meridian 
locations or in arbitrary fixed control points. Four weeks after treat- 
ment, 65 percent of the" patients reported little or no reduction in the 
intensity of their pain, 17 percent reported a 50 percent reduction 
and 18 percent reported at least a 75 percent reduction in their pain. 

Also, the use of new inhalation anesthetic agents with significantly 
less renal and hepatic toxicity have been initiated at a number of 
VA hospitals. In a study of the metabolism of enflurane, isoflurane, 
and methoxyflurane, VA investigators at Palo Alto. Calif, found 
that solubility of the anesthetic in the tissues is the most important 
influence in the readiness with which these anesthetics are metabolized. 
All three are metabolized in vivo — in the living body — to inorganic 
fluoride, by the stimulation from the enzyme fluorinase. Enzyme induc- 
tion with phenobarbitol in rats enhances defluorination of methoxy- 
flurane but does not enhance defluorination of enflurane or isoflurane. 
The fact that the latter are 5 to 10 times less soluble in most tissues, 
including fat, than is methoxyflurane, is believed to explain the 
difference. 

Palo Alto VA investigators also report that clinical neuroscientists 
are intensely interested in cerebral blood flow and metabolism be- 
cause of two independent advances: (1) Recognition that cerebral 
blood flow is not uniform throughout the brain, and regulation of 
blood flow to areas known to lack normal blood supply may be lost 
or may be different from that prevailing in the normal brain, (2) the 
technique of measuring cerebral blood flow in different regions of 
the brain. Of several, the greatest clinical applicability involves the 
injection of a diffusible isotope (radioactive substance which may 
be traced) into a carotid artery which supplies the brain, and the 
subsequent measurement of the rate of decay of isotope's radioactivity 
by collimator probes placed about the head. These probes may be 
focused on desired cross-sectional planes within the brain. While rela- 
tively simple to operate the equipment is not yet readily available 
because of its high cost. 

The choroid plexus and its role in the elaboration of cerebrospinal 
fluid (CSF) are highlighted in a study of cerebral circulation at the 
Albuquerque, X. Mex., VA Hospital. This VA investigator reports 
that major interest in the choroid pleuxs has centered around its role 
of primary responsibility for the secretion of CSF. The most im- 
portant finding, however, has been the proven ability of choroid plexus 
tissue to bidirectionally transport a number of biologically important 
substances. He suggests that the choroid plexus acts as a miniature 
kidney and together with the blood-brain barrier regulates the en- 
vironment of brain cells. 

Medical investigators at the VA Hospital, Washington. D.C. studied 
the interaction of gallamine and pancuronium with tubocurarine, a 
neuromuscular blocking agent, in morphine-nitrous oxide anesthesia. 
They found that gallamine gave the fastest onset of anesthesia and 
that curonium appeared to be six to seven times as potent as tubo- 
curarine at the above-average dosage levels. Both the magnitude and 
duration of the action of both drugs were significantly greater after 
prior administration of tubocurarine. 



80 

A new method using short-acting hypotensive anesthesia is being 
evaluated presently at the VA Hospital, Houston, Texas for critical 
neurosurgical procedures. Transport mechanisms of the choroid plexus 
are being investigated for the evaluation of cerebrospinal fluid me- 
chanics and function for the treatment of hydrocephalus. 

Coronary artery bypass is being prospectively and objectively eval- 
uated for the treatment of angina pectoris and for the prolongation 
of life in cardiac patients at several VA hospitals. 

The dissolution of gallstones by purely medical treatment with bile 
salts and fat solute emulsifiers is being tested by the group at Salt 
Lake City. Utah. They found that the best combination among fat 
solute emulsifiers was equal parts of unconjugated deoxycholate 
with lethicin solution with the individual bile salts in physiological 
concentration. 

In the use of applied mechanical devices, new electronic pacemakers 
for the bladder in veteran paraplegics at Boston, Mass. and Minnea- 
polis, Minn, are being tested. The Minneapolis surgeons report the 
successful implantation of a Mentor bladder stimulator and a pelvic 
floor stimulator in each of two patients with urinary incontinence 
and chronic urinary tract infection due to meningomyelocele. Elec- 
tric stimulation emptied the bladders of both patients with low res- 
idual urine in each case. One patient has sterile urine off medication 
and the other patient's urinary infection is easily controlled with 
medication. Studies in cardiac pacemakers are continuing to progress 
with thermopile nuclear implantable devices as well as new concepts 
in the maintenance of cardiac function. The experience of two years 
by surgeons at the VA Hospital, Buffalo, N.Y. coincides with a 
worldwide experience of nearly four years indicating a high degree 
of reliability in an atomic pacemaker — the Metronomic-Laurens- 
Alcatel isotopic cardiac pacemaker. Performance data indicate a po- 
tential pulse generator life of 20 years for the pacemaker. Less 
expensive, non-nuclear power sources can be expected to satisfy the 
five-to-ten-year requirements of 85 percent of the patients requiring 
a pacemaker. 

Also, a pulsatile intra-aorta balloon counterpulsation for cardiac 
resusitation is being studied as a cardiac assist device which is prac- 
tical now for clinical use. Surgeons at the Denver, Colo. VA Hospital 
report a simple, safe and effective method of producing pulsatile flow 
during cardiopulmonary bypass surgery. They have used intra-aortic 
balloon pumping (IAMP) in 56 patients with no complications 
ensuing. 

An ingenious, simple, new shunt operation is being evaluated for 
the treatment of intractable ascites using a new implantable valve 
at the VA Hospital, Brooklyn, N.Y. and other VA centers. The pro- 
cedure consists of a minor surgical operation for ascites, wherein a 
specially designed one-way pressure activated valve is implanted to 
create a permanent peritoneo-venous shunt. 

In conclusion, the VA system represents leading research in sur- 
gery that continues to add to medical progress as a spin-off to many 
areas in basic as well as clinical research, in addition to producing 
advances in specific surgical problems. 



81 
Vision 

In 1975 the National Advisory Eye Council identified five major 
visual problems: cataract, retinal and choroidal disease, glaucoma, 
corneal disease, and sensory and motor disorders. Research in VA 
hospitals includes investigations in each of these major problem areas 
as well as in an area unique to the VA ; that of blind rehabilitation. 
VA research pioneered the development of prosthetic devices to assist 
blind patients, including a laser cane. 

Investigators at the VA Hospital, Washington, D.C. studied the 
difference in the adhesion between retinal layers in the light- and 
dark-adapted state in experimental animals. This information is of 
benefit in the treatment of patients with detachment of the retina. At 
the VA Hospital, Wood, Wis., pioneering work was done on the 
cornea of the human eye including experiments on animals eyes and 
on ways to improve the preservation of eyes for corneal transplanta- 
tion. In comparing serum-versus eve-bank-storage of animal corneas, 
they found that the endothelial cells remained viable longer in the eye- 
bank-stored corneas than in the serum-stored corneas. They also 
studied the effect of tranquilizing medication on the vision, a par- 
ticular^ important problem in the VA with the many neuropsy- 
chiatry patients receiving these drugs. 

Investigators at the VA Hospital, Gainesville, Fla., have studied 
the basic mechanism of protein movement within the optic nerve in 
hopes of gaining a better understanding of the disease glaucoma. 

Researchers at the VA Hospital, Miami. Fla. have studied eye move- 
ments in order to understand better the sensory and motor disorders 
of the eye. Recent expansion in the use of eye movement recording 
techniques is providing evidence of ocular motor system dysfunc- 
tion heretofore evaluated only by clinical observation. These investi- 
gators have found that pathologically slow segmental velocities in eye 
movement occurred only in patients with neurologic diseases such as 
dystrophy, atrophy and palsy. The method may become a useful tool 
in the diagnosis of the pathologic state. 

Other investigators at the same hospital have studied the blood flow 
in experimental animals as it varies with the amount of oxygen the 
animal received — a study important in the understanding of visual 
mechanisms and the care of patients. In another study, using monkeys, 
a gas (sulfur hexafluoride) has been applied in the attachment of the 
retina. The fact that the gas remains in the eye twice as long as air, 
has allowed sufficient time for the retina to develop a firm adhesion 
to the treated choroid and pigment epithelium. Xo toxic effects were 
observed. 

Vitrectomy, which is the removal of the vitreous jelly within the 
interior of the eye under microscopic control with very fine specific 
instruments, was pioneered at the Miami VA Hospital. 

Studies at the VA Hospital, Sepulveda, Calif, have produced bio- 
chemical information in the understanding of the cells of vision in 
the retina of experimental animals. Researchers at the VA Hospital, 
Boston, Mass. have reported on the effect of agents used to reduce 
inflammation of a specific layer in animal eyes. This type of research 



82 

is helpful in understanding ways of combating inflammation within 
the eye. 

Investigators at the VA Hospital, Little Rock, Ark. reported on 
changes within animal eyes when they were treated with laser beams. 
Pressure measurements are important in understanding potential 
hazards of laser treatment and a better understanding of their 
mechanisms. 

Work at the VA Hospital, San Francisco, Calif, provided insight 
into a possible mechanism of visual decrease following the treatment 
of glaucoma in patients who have had cataract surgery. At the same 
hospital, investigators have developed a more organized way of pro- 
tecting delicate instruments used in eye surgery and have pointed out 
the hazard of all aluminum cans in causing eye injuries. At the VA 
Hospital, San Diego, Calif., new ways have been developed to study 
the pressure in the eye in hopes of better understanding glaucoma 
as well as studying a comparison between the eyes of animals and 
humans. The same investigators reported the effect of a new tech- 
nique for cataract extraction on the cornea and a better understanding 
of possible complications and ways of preventing them. 

MULTI-HOSPITAL RESEARCH 

Cooperative studies 

Cooperative studies are those joint programs in which investigators 
from different VA field stations agree to study collectively any 
selected problem in a uniform manner with identical records and a 
single group report. Cooperative studies are uniquely appropriate to 
the VA because they make use of the largest volume of clinical mate- 
rial under the auspices of any single agency. The device of cooperative 
studies is available to investigators who wish to use it to answer 
appropriate questions in clinical areas. 

The VA is a part of the general United States health care system 
involving both the Federal government and the public. Public Law 
89-785, passed in November 1966, indicated that the VA is a part 
of the community and is to share with and be shared by the com- 
munity. This is one fundamental principle upon which VA conducts 
the various cooperative clinical studies described below. A list of the 
participants in these studies appears in Part II, Data Supplement. 

Cooperative studies in cancer 

1. Lung cancer theory 

This cooperative study group, formed in 1957 and begun in 1958, 
currently has 18 participating VA hospitals. Over 9,000 patients have 
been studied in thirteen controlled clinical trials Under the principal 
investigators in VA hospitals. A pathology panel of three distin- 
guished pathologists reviews and classifies all histologic material. 

Current studies 

The fourteenth study compares three drug combinations: cyclo- 
phosphamide plus (VXr. cyclophosphamide plus adriamycin, and 
CCNU plus adriamycin. If the disease progresses, treatment is 



83 

changed to one of the other two combinations. Patients are stratified 
by performance status, prior therapy and measurable diseases; the 
results are analyzed using these variables and cell type. Therapeutic 
effect is measured by survival, changes in size of measurable and 
e valuable lesions, and occurrence, if any, of new metastatic disease. 
Approximately 332 patients will enter this study before it is completed 
during fiscal year 1976. 

The fifteenth study involves patients with limited disease whereas 
the fourteenth is confined to extensive disease patients. The fifteenth 
study compares short courses versus long courses of irradiation with 
and without low dose prophylactic irradiation to the brain. Results 
will be evaluated on the basis of long-term survival, relapse-free 
period and tumor response. The 240 patients needed to detect a 50 
percent increase in relapse-free survival will be studied in the 18 
months after March 1975, when the work began. 

Accomplishments to date include: (a) validation of the World 
Health Organization classification of cell typing; (b) determination 
that extent of disease, cell type and initial performance status are 
factors in determining survival and perhaps response to treatment; 

(c) demonstration that cyclophosphamide in extensive disease and 
radiotherapy in limited disease give better survival than placebo: 

(d) evidence in the thirteenth trial that CCXU plus cyclophospha- 
mide appears to have a slight advantage over cyclophosphamide 
alone; (e) demonstration in the current fourteenth study appears that 
adriamycin in combination with either cyclophosphamide or CCXU 
has a beneficial effect on squamous and poorly differentiated squamous 
cell types; and (f) development of a method of predicting survival 
based on the demonstrated important predictor variables so that fewer 
patients may be needed to assess new therapeutic regimens. 

2. Surgical adjuvant cancer therapy 

The activities of the VA Surgical Adjuvant Cancer Therapy Group 
have continued during the past year with accrual of patients in five 
separate studies. In addition, followup of all patients remaining in 
previous protocols has continued. Membership in the group was^ad- 
justed during the past year. Two members withdrew, three new mem- 
bers were added and two additional hospitals are probational. 

The present status of the work is as follows: Total number of 
patients screened— 27,115 ; total entered into studies— 9.231 : entered 
during past year — 177 ; total living patients under observation— 1.815 : 
and total patients living more than 5 years — 1,043. 

In addition, final observation of the ten-vear followup of the 392 
patients with lung cancer in the YA-Armed Services Solitary Pulmo- 
nary Xodule Study was completed. 

Ongoing trials 

1. Lung.— For this trial a combination of CCXr and Hvdroxv- 
urea, both given orally, has been used. A total of 262 patients have 
been entered into this study, 170 during the past vear. Plans are now 
underway for use of a different drug regimen, possibly incorporating 

2. Colon,— X combination of Methyl CCXU and 5-FU is used for 
patients randomized to receive the drug in this trial. A total of 235 
patients has been entered, 152 during the past year. 



84 

3. Rectum. — Patients with low-lying lesions with planned abdom- 
inoperineal resection are randomized to receive preoperative radio- 
therapy. Ninety-two patients have been entered into this study, 60 
during the past year. 

4. Stomach.— A combination of Methyl CCNU and 5-FU is used in 
this trial which began in the latter part of 1974. Only 31 patients 
have been entered thus far. 

5. Pancreas. — A combination of CCNU and 5-FU is used for pa- 
tients in this study. One hundred fifteen patients have been entered 
thus far, 64 during the past year. 

3. Urological research group 

The Prostate and Bladder Studies continued admitting patients. 
However, no analyses of the results are available to support state- 
ments at this time. 

The Prostate Study III is treating early cancer of the prostate with 
radical prostatectomy plus placebo or placebo alone. Advanced pros- 
tatic cancer is being treated by Premarin, Provera, stilbestrol, and 
stilbestrol plus Provera. 

The Bladder Study II has been treating early cancer of the bladder 
with transurethral resection of the bladder with the addition of top- 
ical thio-TEPA, oral pyridoxine, or placebo. 

When data from these studies have been processed, a report of the 
findings will be published. 

4. Brain tumor cooperative group 

Five YA hospitals are participating in the Brain Tumor Study 
Group: San Francisco, Calif.; Durham, N.C. ; Indianapolis, Ind. ; 
New York, N. Y. ; and Lexington, Ky. 

The total of 107 patients randomized for treatment in these 5 hos- 
pitals in the late stages of the study compares favorably with the 
numbers submitted by other non-YA participating institutions. These 
patients were distributed equally for treatment of malignant astro- 
cytomas with: (1) Methyl CCNU; (2) radiation therapy: (3) BCNU 
and irradiation; and (4) Methyl CCNU and irradiation. 

Results of the study to date are comparable to the results of the 
previous late stages. Survival is best among the patients treated with 
a combination of BCNU or Methyl CCNU and irradiation. The next 
best survival is among patients treated with radiation alone and the 
shortest survival is among patients treated with Methyl CCNU alone. 

An earlier stage involved evaluation of patients with malignant 
brain tumors. Half of these patients were randomized for treatment 
with Streptozotocin ; the other half were randomized for treatment 
with Adriamycin. Increasingly, patients are referred for treatment to 
the study from other YA hospitals. 

Only preliminary data representing patients randomized are avail- 
able for analysis at this time. The maximum response rate for 
Streptozotocin is 25 percent; for Adriamycin it is 30 percent. While 
the response rates of these two drugs compare unfavorably with that 
of BCNU (63 percent), they compare more favorably with the rate 
of 37 percent for CCNU and 48 percent for Procarbazine. The data 
are preliminary and require correlation with the national figures, a 
process now underway in the Brain Tumor Study Group Central 
Office. 



85 

Computerized tomography (CT Scan) has been available for a year 
and a half and has proven useful in the diagnosis, evaluation and 
management of patients with malignant brain tumors. A study is 
in progress to determine whether the CT Scan will prove useful in 
predicting tumor recurrence. 

5. Radiotherapy versus surgery or delayed hormonal therapy in 
treatment of prostatic carcinoma 

This study on the evaluation of radiotherapy in the management of 
prostatic carcinoma was begun in the previous fiscal year. The prime 
goal of the study is to determine the effect of radiotherapy versus 
delayed endocrine therapy in the management of nonsurgical (in- 
operable) prostatic adenocarcinoma and to evaluate the role of radio- 
therapy versus radical prostatectomy in the management of surgically 
excisable prostatic adenocarcinoma. Simultaneously, the staging bene- 
fits of radioisotope bonescanning, pedal lymphangiography and pelvic 
lymph node sampling are being determined. 

Cooperative studies in internal medicine 

1. Antihypertensive agents 

Study 6. — During the past fiscal year, recruitment of patients con- 
tinued and as of December 31, 1975, 451 patients had been randomized. 
A decision was made by the Operations Committee to discontinue 
randomization since a sufficient number of patients had been obtained. 
The study is designed to compare the efficacy of propranolol alone and 
in combination with other antihypertensive agents ; namely, hydrala- 
zine and hydrochlorothiazide, with the know effective regimen of 
reserpine and hydrochlorothiazide. 

Patient-care personnel at each participating hospital have been 
trained at the \ A Hospital, Washington, D.C., in the fundamentals 
of hypertensive disease — its treatment, morbidity, etc. They have 
been trained to supervise the Hypertension Clinic at their facility 
under the guidance of a staff physician, and in the methods of record- 
ing certain technical data such as ECG's, phonocardiograms, and 
carotid pulse tracings, which are essential to the study. 

Patient intake and followup has been completed; data analysis is 
underway and results will be prepared for publication in the next 
fiscal year. 

Study 7. — This is an investigation of Bethanidine, a drug claimed 
to offer several advantages over those currently available in the treat- 
ment of moderate to severe hypertension. It is a double-blind out- 
patient trial to compare Bethanidine with Guanethidine in patients 
with an average diastolic pressure of 100-124 mm Hg while on Hydro- 
chlorothiazide. It is expected that this study will help to define the 
relative advantages of the two drugs in the management of the more 
severe forms of hypertension. 

The recruitment of patients was terminated a year ago. Slightly 
more than half of the projected sample size was obtained. This will 
enable analysis of data at a slightly lower level of discrimination than 
was initially planned; however, the data will still yield information 
of considerable clinical importance. The monitoring of observations 
was continued until the end of the fiscal year, enabling all patients 
who stayed on treatment to complete at least six months of followup. 



86 

The results will be analyzed during the next fiscal year, and a publica- 
tion prepared. 

Study 8. — This study is a sequel to the previous VA Cooperative 
Studies on Antihypertensive Agents which demonstrated that treating 
men with diastolic pressures in the range of 105 to 115 mm Hg 
markedlv reduced the major complications of hypertension (JAMA, 
August 17, 1970). 

This trial, funded jointly by the National Heart and Lung Institute 
and the VA, began in November 1973 in four hospitals, and random- 
ization of subjects terminated this year. The trial was designed to test 
the feasibility of enrolling and following relatively 3 7 oung Americans 
(25 to 50 years of age) with mild and uncomplicated hypertension 
(diastolic pressures of 85 to 105 mm Hg) . 

It is hoped that the information will be useful in planning and im- 
plementing a successful full-scale study designed to determine whether 
treating mild uncomplicated hypertension will reduce heart attacks 
and strokes, and at the same time to define the price in terms of side 
effects which are always associated with therapy. 

2. Hepatitis 

Posttransfusion hepatitis I and II. — The VA has been conducting a 
series of cooperative studies designed to evaluate the efficacy of various 
forms of gamma globulin as prophylactic agents against hepatitis. The 
first of these, an evaluation of posttransfusion hepatitis, was initiated 
in January 1969 and completed in February 1973. In that study, con- 
ventional gamma globulin was compared, using a double-blind, 
randomized method, with an albumin placebo in 2204 patients. 

With the demonstration that almost one-fourth of the cases of hepa- 
titis which developed were of viral B origin, i.e., positive for the hepa- 
titis B surface antigen (HBsAg, Australia Antigen), it was elected to 
repeat the study and compare the effectiveness of hepatitis B immune 
serum globulin (IIBIG, containing antibodies against viral B hepa- 
titis) with the original gamma globulin. This study has just accepted 
its last patient (a total of 1000 patients). A 6-months foliowup period 
is required for final analysis of the results. 

Needlestick he pa tit H 's.— -The hyperimmune gamma globulin is also 
being evaluated in the setting of accidental exposure, by a needlestick 
or by ingestion, to material infectious for viral B hepatitis. This study 
includes primarily medical and paramedical personnel. The study 
terminated this year with the accession of 553 patients. 

Over 100,000 specimens of senun fo&ve been collected in nil three 
studies and stored in deep freeze for additional serological studies. The 
studies evaluating IIBJG are being conducted in collaboration with the 
National Institute of Allergy and Infectious Diaseses. 

Ifc /K'l'tJ.s In drug abuses. — .V collaborative study has been conducted 
in three VA hospitals to investigate nonsymptomatic parenteral nar- 
col ic addicts for evidence of hepal ic disease. This study was terminated 
this year with almost 600 patients having been entered. A large num- 
ber of biochemical, serologic and immunologic tests are being evalu- 
ated at regular intervals. Liver biopsies are performed if specific ab- 
normalities arc detected for ;> defined period of time. Almost 90 per- 
cent of the patients have demonstrated at one time or another, evidence 
of past Or present viral B hepatitis or Other liver disease, primarily 



alcoholic in origin. Continued followup and additional testing of the 

specimens of stored sera is in progress. 

3. Crohn's disease 

The National Cooperative Crohn's Disease Study continued intake 
and followup of patients: 548 patients had been entered in the study 
as of the end of the fiscal year. The study, supported by the National 
Institutes of Health and the VA. tests the therapeutic and prophy- 
lactic effectiveness of two agents currently in use | Salazopyrine and 
Prednisone) and seeks to provide a basis for judging the usefulness of 
azathioprine in treatment of this disease. Preliminary results are ex- 
pected during the next fiscal year. 

Cooperative studies in mental health and behavioral sciences 

1. Social sciences 

Two cooperative studies are underway. Both are controlled evalua- 
tions of outplacement programs for psychiatric patients. 

The evaluation of foster care by patient attitude anal behavior, — The 

aim of this study was to determine effectiveness of foster care prepara- 
tion and placement. 57^ subjects from 5 hospitals were randomly as- 
signed to foster care preparation (experimentals) or continued hos- 
pitalization (controls). They were studied before assignment, at place- 
ment of experimentals. and 4 months later regarding social function- 
ing, mood, activity, and overall adjustment. Hospitals averaged 2 
months preparing experimentals. resulting in 73 percent placed in 
foster care. Data collection on the foster care study has been completed 
and findings submitted for publication. A one-year followup of the 
patients will be analysed in the coming year. 

The evaluation of day treatment care by patient attitude and oe- 
\or. — Intake of subjects in this study ended with 162 patients from 
10 AW centers. The subjects averaged 37-38 years of age. about half 
had never married, and half listed parents as next of kin. The average 
number of prior hospitalizations was four and patients averaged 155 
days in the hospital during the year preceding their referral to day 
treatment. The Day Treatment Study completed patient intake this 
year and a two-year followup remains. 

2. Drug-abuse prevention 

The LA AM ^methadone study, — This study is a joint effort by the 

VA and the AVhite House Special Action Office for Drug Abuse Pre- 
vention ( SAODAP) to evaluate the relative safety and efficacy of 1- 
alpha acetyl methadol < LA AM ) and methadone. LAAM has clinical 
effective range of 48-72 hours in contrast to methadone's 24 hours. This 
could substantially reduce the take-home doses and its consequent 
street diversion and accidental poisoning. Logistic-ally a three-time- 
per-week clinic visit schedule vs. daily schedule could also mean a 
substantial increase in a clinic's treatment capacity. Less frequent 
medication may also help to de-emphasize the issue of chemicals in 
the course of rehabilitation. 

A secondary goal of the project was to compare two doses of metha- 
done (50 mg vs. 100 nig) for maintenance therapy. Patient- were 
randomly assigned to one of the three study groups viz methadone 50 
mg. methadone 100 mg and LA AM SO mg. The study was double- 
blind, with a study period of forty weeks" for each completer. 

70-709 — 7C S 



88 

Intake of patients began in April 1973 in three pilot hospitals: 
Sepulveda and Brentwood, California; and St. Louis, Mo. The last 
patient completed the study in March 1975. A total of 430 patients 
from twelve VA hospitals participated in the study. Data collection 
is now complete and detailed analyses are being carried out. One or 
more manuscripts will be forthcoming. 

3. Characteristics of effective psychiatric programs 

Although treatment teams in psychiatric hospitals introduce the 
kinds of programs they feel are most effective, very little definitive 
research has been carried out to identify the characteristics of effec- 
tive programs. 

The primary purpose of this project is to identify the program 
dimensions characteristic of effective programs. If the therapeutic in- 
gredients of effective psychiatric programs can be identified and ver- 
ified in a subsequent controlled study, the application of these findings 
to VA psychiatric hospitals could result in the same kinds of im- 
provements in treatment effectiveness that occurred with the introduc- 
tion of tranquilizing drugs. The design of the study requires data col- 
lection on both program characteristics and program effectiveness 
from a large number of psychiatric treatment units in VA hospitals. 

The pilot study for this project began in February 1975. Data was 
collected at all hospitals between May and October 1975. Nineteen 
hospitals are participating in this study. Measures of program effec- 
tiveness and program characteristics will be collected on about 100 
treatment wards. 

Cooperative study in pulmonary diseases 

Chemoprophylaxis of tuberculosis 

In January 1965, a study was started with the aim to investigate 
the ability of Isoniazid (INH) to prevent reactivations of pulmonary 
tuberculosis in patients with the inactive form of this disease. Eleven 
VA hospitals participated and recruited a total of 7,035 patients 
for the study. 

The patients w r ere randomized into three groups. One group was 
given INH daily for two years, another group INH for one year 
and a third group received no INH. Placebos were also used in the 
double-blind study. The study ran from 1965 to January 1, 1974. 

Data analyses are underway and manuscripts will be prepared for 
publication. 

Cooperative study in speech pathology 

Treatment of aphasia 

The Cooperative Study on the Effects of Speech and Language 
Therapy on Kecovery from Aphasia, initiated in July 1973, is de- 
signed to evaluate the efficacy of two different types of treatment for 
patients who experience speech and language disorders subsequent 
to sustaining a left hemisphere cerebral vascular accident. Speech 
Pathologly and Neurology Services in five VA hospitals are partici- 
pating in the study. 

Patients who meet the general criteria for admission to the studv 
are assigned randomly to receive either the traditional treatment or 



89 

nontraditional treatment. Patients in the traditional treatment group 
receive from four to eight hours of individual therapy each week. 
Patients in the nontraditional treatment gTOup receive from four to 
eight hours of group therapy each week with no direct manipulation 
of speech and language. All patients receive other rehabilitative 
therapy (physical therapy, occupational therapy, etc.) if prescribed 
by the attending physician. 

During the first year of the study, it became evident that study 
patient intake was a serious problem. During the second year, patient 
intake has improved dramatically. It was determined that a sufficient 
number of study patients could" be- obtained if intake was extended 
for one additional year. The requested extension was approved. There- 
fore, it appears an adequate sample of study patients will be obtained 
to meet the objectives of the study. 

Cooperative studies in surgery 

1. Analgesics 

The VA Cooperative Analgesic Study is now in its twelfth year 
of operation, with five participating hospitals: Boston, Bronx. Los 
Angeles, Miami, and Palo Alto, the core facility. The aims of the 
cooperative study are to establish clinically the relative potency and 
side-elfect liability of new and marketed analgesics and sedatives and 
to refine further the methodology for this type of research. 

In this past fiscal year, two analgesic bioassays and three dose- 
ranging studies were completed. 

Bioassays. — (1) Both morphine and codeine have been used for 
some years in analgesia studies as standard or reference drugs, mor- 
phine in parenteral and codeine in oral studies. Since codeine is also 
frequently used parenterally, we undertook a study to determine the 
relationship of these two standards to each other when administered 
parenterally in postoperative pain. Although there was incr< 
response with increased dose for both drugs, the high dose of codeine 
(60 mg) was less effective than the low dose of morphine (5 mg), 
so a further study is underway comparing 5 and 10 mg of morphine 
with 60 and 120 mg of codeine (2) Meperidine is a very widely used 
analgesic, yet there is still considerable controversy regarding its 
overall potency relative to morphine and its time course of action. In 
the second of two studies, we compared 5 and 10 mg of morphine 
with 37.5 and 75 mg of meperidine (doses commonly used for pain 
relief) in 117 patients. These doses proved to be equipotent for peak 
(maximum) analgesia. However, our earlier study showed that for 
comparable total analgesia (averaged over a time" span of 4 hours), 
higher doses of meperidine (50 and 100 mg) are necessary. 

2. Coronary arterial disease 

The intake of patients into this cooperative study has now been 
completed. Over 1.000 patients have been entered into tnis prospective 
randomized study, designed to answer the question whether aorto- 
coronary saphenous vein bypass grafting has a beneficial effect on 
mortality, morbidity, and quality of life. Approximately 500 patients 
have been randomized into the medical treatment group and 500 into 



90 

the surgical treatment group. This type of study had been advocated 
by most responsible cardiologists and surgeons throughout the coun- 
try, but it is the only large-scale study of stable angina which has been 
concluded, and is now in the followup stage. 

Data from the study are now undergoing analysis. The following 
types of analyses are currently underway : analysis of the screening 
and coronary angiographic log data; review of the coronary arterio- 
grams; review of electrocardiograms, which are being subjected to 
computer analysis; assessments of quality of life including angina 
questionnaires, treadmill tests, and morbidity data; review of opera- 
tive procedures, and assessment of operative morbidity and complica- 
tions; analysis of the opacification of vein bypass grafts and correla- 
tions with the outcome; a study of the previous subset of implant 
patients; and finally the major analysis of the 1,000 patients, breaking 
them into various subsets of patients with similar characteristics. 

3. Esophageal and gastric varices 

This year has been spent doing the final analyses of data from the 
277 patients, and the analyses for risk factors of the re-bleeders among 
the 77 patients in the medically randomized group. Some "whys" and 
"don'ts" for patients who do not re-bleed, and for patients who do re- 
bleed, and for patients who are treated with portacaval shunt are 
emerging. It appears that it is possible to identify a potential re- 
bleeder who should have a portacaval shunt to prevent re-bleeding. 

The in-put into the computer of quality-of-life data in the overall 
study for all patients also has been completed. 

4. Bowel preparation for colon operations 

The purpose of this study is to determine whether giving antibiotics 
by mouth in addition to routine bowel preparation before operation 
can reduce the chance of wound infections and mortality in patients 
undergoing resection of the large bowel. This is a prospective random- 
ized double-blind clinical trial conducted in nine VA hospitals, de- 
signed to collect data on approximately 500 patients over a two-year 
period. Senior surgeons have been selected at each of the nine hospitals 
to supervise the study and nurse epidemiologists are being selected to 
carry out the observations in each hospital. In eight of the nine hos- 
pitals careful special bacteriology studies will be done of the bowel 
content, postoperative stools, and any infections to determine if the 
antibiotics have suppresed dangerous bacteria. 

Cooperative study in pathogenic significance of sickle-cell trait 

This study, being performed in 13 VA hospitals, was designed to 
determine whether the frequency of the sickle-cell trait declines in the 
older age groups and whether the sickle-cell trait in the presence of 
certain clinical conditions might be a life-endangering risk that in- 
creases with age. The hypothesis will be tested that individuals with 
the sickle-cell trait have greater susceptibility to pulmonary infarc- 
tions, pyelonephritis, vascular complications of diabetes and post-op- 
erative thrombotic complications. 

The study will include approximately SO. 0(10 individuals. The data 
thus far obtained on approximately 65,000 veterans have been analyzed 
with regard to the dependence of the frequency of the sickle-cell trait 
on age. The relationship of the trait to longevity, morbidity and sever- 



91 

irv of certain diseases will be investigated during the next year. The 
risk of deficiency of the red blood cell enzyme Glucose-6-Phosphate 
Dehydrogenase alone and combined with the sickle-cell trait will be 
a.-.-essed in a similar way. 

Cooperative study on aspirin therapy and unstable angina 

This is a prospective, randomized, double-blind clinical trial con- 
ducted in 11 VA hospitals to determine whether small doses of aspirin 
can decrease morbidity and mortality in patients with unstable angina. 

A pilot activity was conducted to detect and correct problems before 
official intake began. Experience with these 50 patients demonstrated 
that the study is logistically feasible and systems for shipping and re- 
ceiving samples for enzyme analysis and data flow were established. 
It also demonstrated that there were no problems in obtaining patient 
consent and no difficulty in eliciting the patient's compliance. 

The Central Laboratory is currently running approximately 400 
tests (total CPK. LDH/SGOT, CPK, and LDH isoenzymes", and 
cholesterols) each week. The participating laboratory technicians are 
trained in the techniques of platelet aggregation and enzyme analysis. 
Computer analysis of data is in progress. It is planned for the study 
to continue until the goal of 1480 patients is reached. 

Cooperative study in vasodilator therapy of myocardial infarction 

Ten hospitals have now been funded for participation in this study. 
Eight of these are now randomizing patients and two are recruiting 
personnel and acquiring the necessary equipment. Approximately 40 
patients have already been randomized to date. 

Cooperative study of quality control of lab data 

The accuracy and precision of routine chemistry and hematology 
determinations were evaluated in 20 highly automated VA hospital 
laboratories. 

In general, the laboratories were found to be performing at the level 
of "the state of the art" and. more importantly, meeting realistically 
a criteria for "Medical needs'' for most routine tests. Xormal value 
data showed that it is valid to pool normal values from different labora- 
tories when non-random variables, such as different methodology or 
equipment have been eliminated. 

Cooperative study on drugs and sleep 

This project began at the start of fiscal year 1975. It is a serial- 
study project designed to provide a detailed description of the com- 
parative neurophysiological sleep EEG-EOG. subjective, and psy- 
chological effects of two sedative hynotics. a benzodiazepine and a bar- 
biturate. The first study aims for standardization of procedures among 
the three participating laboratories. Each hospital will study six nor- 
mal men for three consecutive nights each. The second study is designed 
to allow determination of equivalent drug doses for the two study 
drugs. In the third and primary study. GO men with primary insomnia 
will be evaluated in a 28-day protocol, The protocol includes laboratory 



92 

adjustment, baseline, initial placebo, drug and withdrawal placebo 
conditions. Patients in the five treatment groups will receive a high 
dose of the benzodiazepine, a low dose of the benzodiazepine, a high 
dose of the barbiturate, a low dose of the barbiturate, or placebo, re- 
spectively, during the drug period. 

NAS-NRC FOLLOWUP AGENCY 

Studies with the National Academy of Science-National Research 

Council 

The Medical Follow-up Agency is an activity within the Assembly 
of Life Sciences of the National Academy of Science-National Re- 
search Council. The function of the Agency is to help medical investi- 
gators to utilize the records systems of the Veterans' Administration 
and of the Armed Forces in order to facilitate or to accomplish studies 
in the natural history of disease, prognosis, etiology, therapeutic ef- 
ficacy, or others to which these records resources may be appropriate. 

The Agency Avas established following World War II. The program 
was envisioned as having great potential in view of the large size of 
the military-veteran population, the relatively good documentation of 
medical and environmental history during wartime, the ease of rep- 
representation sampling, the extensive programs of veterans' benefits, 
and the possibility of linking military. Veterans' Administration, and 
other health records. 

The program is guided by an advisory Committee on Epidemiology 
and Veterans Follow-up Studies. The content of the program, how- 
ever, at any given time reflects primarily the interests of individual 
investigators and sponsoring agencies. The costs of the Agency are 
funded by one or another of these sponsoring agencies, principally the 
Veterans' Administration and the National Institutes of Health. The 
Veterans' Administration, the Armed Forces, and the National Per- 
sonnel Records Center, National Archive Service (GSA) provide es- 
sential support by granting access to the m-ords needed for approved 
projects. The Medical Follow-up Agency of the Assembly provides a 
statistical and logistic competence for planning specific studies and 
assisting individual invest igators in the conduct of those approved 
by the Committee and by the agencies whose records are to be used. 

Projects that were active during the year ending June 30, 1975 
are summarized briefly below. The funding source for each project 
is also shown. In addition to specific funding, basic support is re- 
quired for planning new studies, invest igating records resources, devis- 
ing and testing forms and procedures, conducting pilot studies to as- 
sess feasibility and costs, developing new computer programs, and 
maintaining channels of access to the veteran population and its 
medical experience. Funds for such basic Support arc provided by the 
Veterans' Administration and the National Institutes of Health. 

Studies active during fiscal year 1975 

Survey of mortality of former prisoners of war (Veterans* 
Administration) 

Shortly after World War IT, a study was initiated to examine the 
health of former prisoners of war for evidence of residual impairment. 



93 

Subsequently, the study was extended to include men raptured during 
the Korean War. 

The mortality experience of former prisoners and groups of con- 
trols, traced for 20 years following World War II and for 12 years fol- 
lowing the Korean War, has already been described. Men captured in 
the Pacific in World War II showed evidence of increased mortality 
during eight years following repatriation, as also did former Korean 
War prisoners, but no evidence of impaired survival was seen in the 
European prisoners. These findings were supported by a more recent 
study of morbidity in which excesses in hospitalizations for both 
phychiatric and physical illnesses were seen in the two groups of Pacif- 
ic prisoners, excesses which persisted for eight years and more after 
repatriation. 

Work is currently under way to update the mortality experience. It 
was intended originally to extend the follow-up through 1973, but 
preliminary examination of the numbers of additional deaths identi- 
fied revealed unexplained shortages during the latter part of 1971 and 
early 1972. The Veterans' Administration file is being corrected and 
when this work is complete, the prisoner-of-war and control samples 
will be resubmitted for a mortality update. As a result, it will be pos- 
sible to extend the mortality analysis to the end of 1975, thereby add- 
ing a full ten years of follow-up to the experience reported earlier, 
completing the mortality follow-up to 30 years for the World War II 
component and 22 years for the Korean War samples. 

Surgical adjuvant cancer chemotherapy study (Veterans' Admin- 
istration) 

This cooperative, study group, for which the Medical Follow-up 
Agency serves as the Statistical Coordinating Center, includes the 
surgical services of 27 Veterans Administration hospitals, and was 
organized in 1957 at the request of the National Cancel- Institute to 
determine if certain drugs would improve survival following surgery 
for cancer. The Agency provides professional statistical support and 
has responsibility for the statistical aspects of design of the trials, the 
colledion. processing, analysis, and interpretation of data, and exe- 
cutes the functions of receipt, editing:, and coding of data. 

By .°,1 March 1975, after nearly 18 years of collaboration, a total of 
9.231 patients had been accepted for study, of whom nearly 1,900 are 
still alive and being followed. Initially, the objective of drug therapy. 
administered at and immediately following operation, was to prevent 
Hie cells released into the circulation at operation from metastasizing, 
but when the data were analysed it was clear that failure to cure with 
resection of the gross tumor was due to existing unrecognized distant 
metastases. Attention has tinned to the use of drug therapy, and more 
recently immunotherapy, to control remote disease not included in the 
resection while preoperative X-ray therapy has been used to control 
local spread. There is evidence that this 'last technique is of some 
benefit, to men with rectosigmoid lesions. Accession of patients into the 
following: trials is continuing or will commence shortly: 

(I) Prolonged therapy with CCNTJ in combination with 5-FU 
for carcinoma of the pancreas : 

(-?) Prolonged therapy with CCNTJ in combination with Hy- 
droxyurea for bronchogenic cancer: 



94 

(3a) Prolonged therapy with ME-CCNU in combination with 
5-FU following curative resection of the large bowel: 

(3b) Immunotherapy with Methanol Extraction Residue of 
BCG (MER) added to ME-CCXU in combination with 5-FU 
following a proved incomplete resection of the larger bowel, to be, 
activated in August 1975 ; 

(4) Preoperative X-ray therapy to patients with proven cancer 
who are candidates for an abdominoperineal resection (second 
trial) ; 

(5) Prolonged therapy with ME-CCXU in combination with 
5-FU for gastric cancer ; and 

(6) Immunotherapy with Methanol Extraction Residue of BCG 
(MER) . to be activated in August 1975. 

A seventh protocol to compare radition therapy with surgery for 
cancer of the esophagus is nearing final form. 

Two fairly extensive analyses of data are made each year for publi- 
cation as progress reports. Several additional analyses were performed 
for publication in the medical literature, including: 

(1) A ten-year follow-up of patients with asymptomatic 
solitary nodules ; 

(2) A major study of stomach cases entered by July 1969 in- 
cluding an intensive search for a treatment benefit, for patterns 
of recurrence of disease, and for characteristics of patients and 
disease which are predictive of recurrence; 

(3) A re-analysis of the benefits of preoperative X-ray for 
rectosigmoid cancers, extending complete follow-up to five 
postrandomization years: and 

(4) An analysis of the two colon trials of 5-FU therapy. It ap- 
pears that survival time may be slightly improved in the patients 
to whom drug therapy was assigned. 

Thirty-year clinical follow-up of selected demyelinating diseases 
(Veterans' Administration) 

The objective of this long-term prospective study of multiple 
sclerosis is to describe the course of the disease over a period of 25-30 
years in a sample of nearly 500 cases originally diagnosed in the U.S. 
Armv during World War II. The probability that men with optic 
neuritis will progress to MS or to retrobulbar neuritis without MS will 
also be assessed for a sample of nearly 200 such cases. 

The surviving subjects are being examined nationwide by a group 
of collaborating neurologists and ophthalmologists under the leader- 
ship of Dr. John E. Kurtzke of Georgetown University. Costs of the 
clinical examinations themselves are being defrayed by the Multiple 
Sclerosis Society. 

A.S of •)() .June 1975, after two years of planning and data collection, 
370 men had agreed to be examined and examinations had been com- 
pleted for 221 of these. The third year schedule calls for the comple- 
t ion of all data collection and analysis of results. 

Longitudinal study of cardiovascular disease (Veterans' Admin- 
istration) 

Hillman, Levy, AYhite. and Stroud published in 1944 and 1945 a 
- of papers on blood pressure and hypertension in moiv than 



95 

22,000 Army officer?. Their data were obtained from the annual phys- 
ical examinations which were performed on all officers until, during 
World War II, the program was discontinued. In these studies, Levy 
and his associates showed that heart rate, as well as blood pressure, had 
important predictive value, at least over the short term of a few years, 
especially when both were elevated, even though only transiently. 

The punch cards used by these investigators have been made avail- 
able to the Medical Follow-up Agency. These cards confirm the data 
en initial, final, highest, and lowest blood pressures as obtained from 
the original longitudinal records. Other data, such as height, weight, 
heart rate, presence of albumin in the urine, etc. are also present on 
the punch cards. 

The present study has the purpose of extending the earlier observa- 
tions by including an additional 30 years of follow-up for cardiovasc- 
ular disease mortality. The principal objectives will be to determine 
the duration of the prognostic significance of the indicators identified 
by the earlier investigators and to measure the significance for subse- 
quent mortality of blood pressure, heart rate, and ponderal index, in- 
dividually and in combination. 

Mortality information has been obtained from the Veterans' Admin- 
istration Beneficiary Identification and Records Locator Subsystem 
(BIRLS). About 6.500 deaths have occurred in the group and cause 
of death is being coded from death certificates which are now being 
obtained. 

It is expected that the study will be completed during fiscal year 
1976. 

Microwave cataract screening (Veterans* Administration) 

Since there is concern that chronic exposure to microwave radiation 
may produce cataracts after a long latency period, the feasibility of 
studying radar repairmen who served on surveillance aircraft is being 
explored. A simple cataract viewer has been designed by personnel of 
the Xew Orleans Veterans' Administration Hospital and Tulane Med- 
ical School. Approximately 160 men who served in a Xavy aircraft 
patrol squadron during the Korean War have been selected for a pilot 
study. One hundred and twenty- four men were located, 60 of these 
agreed to participate in the study, and 52 examinations have been per- 
formed. Approximately one-half of the men have reported findings 
which are suspicious, and present plans call for referring all who ac- 
cepted for ophthalmologic examination. 

Monitoring records resources (Veterans' Administration) 

A routine mortality check of the Twin Registry in BIRLS revealed 
a dramatic decrease in numbers of deaths reported in 1971 and what 
appeared to be an under-reporting in 1972. The same condition was 
found to be present in each roster that had been checked against 
BIRLS. Subsequent analysis of date of death showed that the under- 
reporting occurred principally in the last six months of 1971 and pos- 
sibly the early months of 1972. 

Discussions with concerned Veterans' Administration staff revealed 
that the deficiency was not known to the VA ; subsequent consultations 
with personnel of the BIRLS Systems group resulted in the conclu- 
sion that the problem had occurred during the transition period from 



96 

manual to computerized operations and could be remedied relatively 
easily. The Medical Follow-up Agency will resubmit its rosters in 
the near future. 

A potential threat to the use of federal records systems for research 
purposes was raised by the passage by Congress, in December 1974, 
of the Privacy Act of 1974, Public Law 93-579. The wording of the 
law seemed somewhat ambiguous as it applied to the use of records 
for research purposes ; the key would be found in the interpretations 
made by the Office of Management and Budget, Numerous discussions 
were held with officials at the various agencies whose records the 
Medical Follow-up Agency customarily employs and with interested 
members of committees set up by such organizations as the American 
Public Health Association and the New England Cancer Society to 
counter the possible threat to medical research implied by the Act. 

At this writing, although full clarification has not yet occurred, 
it appears that appropriate relief will be found in the "routine use" 
provisions of the Act, under which uses not inappropriate to the 
purpose for which the information was originally collected, may con- 
tinue if declared to be "routine" by the agency possessing the file, and 
so published in the Federal Register. Requests for such publication 
have been made to the three armed services and to the Veterans 
Administration and it is expected that the Agency's privilege of using 
the records will be preserved by this provision. 

Medical genetic studies of veteran twins (National Institutes of 
Health) 

A panel of 15,900 pairs of twin veterans has been established with 
support from the Veterans' Administration and from the National 
Institutes of Health to make possible the conduct of epidemiologic 
and medical genetic studies. The panel became accessible to investi- 
gators in 1967. Since that time a number of studies have been com- 
pleted and reports have been published. 

Using questionnaires and clinical examinations it has been possible 
to control genetic influences in evaluations of the commonly recog- 
nized risk factors of coronary heart disease and of chronic obstructive 
pulmonary disease. A study of changes in ocular pressure following 
topical administration of corticosteroids indicated that this phenome- 
non is not based on a simple genetic mechanism as had been believed 
previously. The influence of genetics in schizophrenia and in effective 
psychosis has been assessed relative to psychoneurosis. An evaluation 
\v;is made of the importance of heredity in several diseases including 
selected dermatologic disorders, multiple sclerosis, and headache and 
in diagnostic indices such as the Type A behavior pattern defined by 
Friedman and Rosenman, the scales of the California Psychological 
[nventory, and the serum levels of Immunoglobulin E. Mechanisms 
of deposition of particles in lungs and their subsequent clearance have 
been si tidied to evaluate the significance of genetics in these processes. 

A current extensive undertaking is a study of the quantitative 
effects of schooling, innate abilities, and family structure on earnings. 
To collect the necessary data, a large questionnaire mailing was made 
to members of the panel. The study is being extended to include 4 career 
information from military service records. Through the questionnaire 



97 

it has been possible to determine the contribution of heredity to 
income and education. The study of military records will make it 
possible to study native ability and also to evaluate the extent to which 
interrelationships of these three variables are influenced by heredity. 
Ascertainment of mortality in the panel through the record system 
of the Veterans' Administration makes it possible to monitor deaths 
due to different causes in the twin panel. Such investigations are under 
way with respect to coronary heart disease, cancer, and other clinical 
entities. The group has now reached an age where a significant number 
of deaths from medical causes occurs each year and continued moni- 
toring of mortality in this group promises to provide valuable infor- 
mation regarding the relative importance of genetic factors in chronic 
and other diseases. 

Epidemiologic study of multiple sclerosis in U.S. military veteran 
population (National Institute of Neurological and Communi- 
cative Disorders and Stroke) 

This study of the epidemiology of multiple sclerosis has two basic 
objectives: (1) to determine, if possible, by focusing attention on a 
group of cases with place of birth and place of induction into the mili- 
tary in different sections of the country (migrants), whether circum- 
stances producing the disease occur closer to birth than to entry into 
service, and (2) to investigate further, achieving more precision 
through the use of large samples of cases and controls, the relative 
importance of the preservice characteristics identified in earlier 
studies as factors distinguishing cases and controls: urbanization, 
socioeconomic status, race, and visual acuity. Also being examined is 
the question whether these factors are equally important among 
females, and whether there is interaction between race and other 
factors. The study of migrants is based upon the known variation 
with latitude of the risk of MS. By drawing upon the several thousand 
veterans of World War II and of the Korean War who were granted 
compensation for MS, a series of 5,300 case-control pairs has been 
-assembled, approximately 10 percent of whom have been identified as 
migrants. Included among these cases is a series of some 175 black 
males and about 185 females. Controls have been selected from a 
roster of National Service Life Insurance policyholders during 
World War II and a 0.1 percent sample of all servicemen during the 
1950-70 period, and have been matched to cases on the basis of age, 
branch of service, and date of entry. 

White male cases and controls number about 4,400 in each group. 
Among these men, case-control ratios for non-migrants of the north- 
ern, middle, and southern tiers, respectively, are 1.38, 0.97, and 0.54. In 
every case, the ratios for migrants fall between those for the tiers 
of birth and induction. 

Socioeconomic status and visual acuity have been confirmed as 
associated factors of risk for the disease among white males in this 
larger sample. Xo case/control differences have been found in the 
preservice incidence of childhood communicable diseases. 

States of induction bearing the highest risk for MS all lie north 
of 39° latitude. Specific counties with the highest risks, whether as 
residences of birth or induction, lie north of 44° latitude and are 



98 

located in the states of Washington, Minnesota, and Maine. A report 
summarizing these and other findings will be forthcoming. 

Epidemiologic and follow-up study of amyotrophic lateral sclero- 
sis and other motor neuron disease (National Institute of 
Neurological and Communicative Disorders and Stroke) 

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron 
disease of unknown etiology, rapidly fatal course, and very low inci- 
dence, about one per 100,000 population per year. A three-part study 
of the epidemiology and natural history of ALS and other possibly 
related motor neuron diseases is in progress. Its purpose is to seek 
factors associated with ALS and to attempt some clarification of the 
essential similarities and differences with these other diseases. 

Parts 1 and 2 are epidemiologic studies ; Part 3 is a natural history 
study. In Part 1, a World War II service record investigation of 500 
veterans of the period who died of ALS during the years 1963-67 is 
being made, comparing these men with controls matched for age, 
branch, and date of entry into service. Data collection and coding of 
this phase is essentially complete. 

The final interview sample of Part 2, designed to elicit more exten- 
sive and detailed information from ALS patients and controls hos- 
pitalized in the VA system, numbers slightly more than 130 cases and 
half as many controls (malignant brain tumor patients). 

A roster of some 2,600 patients discharged from Veterans' Admin- 
istration hospitals during 1957-69 with a diagnosis of ALS has been 
created from two tape files provided by the Veterans' Administration. 
The results of a pilot sample indicate that 750 individuals should be 
selected from this roster in order to realize a sample of 500 patients 
for whom the necessary data on signs and symptoms at onset and 
diagnosis can be obtained for the prognostic study of Part 3. 

Analysis of these samples will probably begin in late 1975. 

Epidemiology of Hodgkin's disease (National Cancer Institute) 

Hodgkin's disease, as suggested by recent epidemiological studios, is 
probably two or three distinct entities, one of which has onset char- 
acteristically between ages 20 and 30. Evidence has also shown that, 
for the disease of early adult life, the risk varies with a number of 
demographic and environmental characteristics, posing an infectious 
etiology as a serious possibility. This study is exploiting the large U.S. 
military experience to investigate the disease in a population of young- 
adult males which is relatively unbiased by social and geographic ori- 
gins and by prior medical history. About 650 men under 31 years of 
age and with at least one year of duty prior to diagnosis in a military 
hospital, in the period 1950-68, have been matched with controls on 
the basis of branch, year of birth, and service entry date. 

This project is now in the analysis phase. Findings thus far con- 
tinue to support the hypothesis of an infectious agent, possibly a "slow 
virus." A strong inverse relationship between the risk of the disease 
and sibship size has been found. In addition, an urban induction resi- 
dence (especially the northeastern I.S.), tonsillectomy prior to in- 
duct ion. and a high score on the military genera] aptitude test increase 
the risk of Hodgkin's disease. The remaining analysis includes a 
Search for space-time dusters of the cases and an analysis of much of 



99 

the data within each of the four major pathologic types of the disease 
obtained from a current examination and reclassification of tissue 
specimens. 

Causes of death following occupational exposure to microwave 
radiation (RADAR) (Bureau of Radiological Health) 

A population-based prospective study has been planned in collabora- 
tion with an investigator at the Bureau of Radiological Health. The 
investigation will make use of occupational differences in levels of 
shipboard exposure to microwave radiation of Navy personnel during 
the Korean War period. Two groups of approximately 20,000 men 
each, one maximally exposed and the other minimally exposed, will 
be compared with respect ro (1) mortality, with attention to specific 
diagnosis, (2) hospitalized illness at the time of occupational expo- 
sure, and (3) later disability. The period of ascertainment will be 
1950-1974 for mortality. 1950 through 1960 for Navy hospitalization, 
and 1963-1974 for hospitalization in Veterans Administration 
facilities. 

Rosters of cases and controls have been built from records of gradu- 
ating classes of Navy Class A schools. Men graduating as either Elec- 
tronics Technicians or Fire Control Technicians were assigned to the 
maximally exposed cohort, while Radio Operators and Radar Opera- 
tors comprise the control cohort. 

Mortality has been ascertained, with some 1,400 deaths reported. 
The cause of death has been determined for about two-thirds of these 
and coding of causes will begin soon. 

Cancer mortality among World War II X-ray technicians (Bureau 
of Radiological Health) 

An earlier study by the Medical Follow-up Agency of 6,500 men 
who were trained as X-ray technicians in the Army during World 
War II and a comparable-sized group of controls (pharmacy tech- 
nicians and medical laboratory technicians) revealed that, during the 
period 1946-1963. the former X-ray technicians had no abnormal mor- 
tality patterns for any disease that could be associated with X-ray 
exposure. 

In recent years, it has become clear that ionizing radiation is a po- 
tent carcinogen and that the latent period for induction of solid tu- 
mors, especially, may be several decades. The Bureau of Radiological 
Health, therefore, has asked the Medical Follow-up Agency to ex- 
amine the more recent mortality patterns in the group included in the 
earlier study to determine whether any X-ray effect had become dis- 
cernible in the period 1964-1974. The rosters have been checked against 
BIRLS, and death certificates are now being collected and coded as 
to cause of death. The study will be completed during fiscal year 1976. 

Epidemiology of childhood cancer, with reference to prenatal 
X-ray (National Cancer Institute) 

Several investigations, with conflicting results, have been made of 
the hypothesis that X-ray doses on the order of one to two rads. re- 
ceived by fetuses while their mothers were having abdominal X-rays, 
resulted in a significantly increased risk of cancer before the age of 
10. Some of the results of previous studies may have been influenced 
bv social class differences between mothers who were X-raved and 



100 

those who were not. It was decided, therefore, to study the question 
among births in military hospitals, where the decision whether 
or not to X-ray the prospective mother would be unaffected by her 
ability to pay, but would be determined almost exclusively by medical 
considerations. 

Name, date of birth, and other identifying information were ob- 
tained from the National Cancer Institute for each of the approxi- 
mately 39,000 children under 18 years of age who died of cancer in 
the United States during the years 1960-1969. The name of the hospi- 
tal in which birth occurred was obtained primarily from the state of 
birth, but in rare instances from hospitals themselves. 

About 1,400 births occurring in military hospitals were thus iden- 
tified and the clinical records for slightly over 1,000 of these were 
located in the files of the National Personnel Records Center in St. 
Louis, Missouri. 

Eecords abstracting for all cases and twice as many controls has 
been completed and the file is being readied for analysis. 

Follow-up studies of World War II veterans with certain condi- 
tions possibly related to cancer (National Cancer Institute) 

Groups of World War II veterans thought to be at differential risk 
for some forms of cancer, as a result of some medical condition or 
operation experienced while in service, have been assembled from the 
hospital admissions files of the Army in 1944 and 1945. 

Two broad groups of studies are in progress. The first, related 
to abnormalities in immunological competence while in service, is 
composed of men having allergies or splenectomy. The other group 
consists of men with any orchidopexy, nephrectomy, or chronic 
alcoholism. 

This investigation, being done in collaboration with members of the 
Epidemiology Branch of the National Cancer Institute, will ascertain 
and analyze mortality of these men and their matched controls to de- 
termine if an excess of mortality from cancer or other causes of death 
exists. 

Probing studies of this type have recently become more feasible be- 
cause the mechanism now exists for relatively inexpensive records 
linkage between the Veterans' Administration files and the military 
hospital admission files, both of which have been computerized. All 
investigations in studies of this nature have a common procedural link 
in that the initial condition is verified from the hospital admissions 
file, and the fact, as well as the certified cause in most instances, of 
mortality is obtained from the Veterans Administration. 

Approximately 34,000 men have been selected for the study. Mor- 
tality ascertainment has been completed, with approximately 7,300 
deaths having been identified. Information on cause of death has been 
obtained for some 80 percent of the deaths and coding of cause of 
death has begun. 

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